Patent Docs

Stem Cells a Go! in California

    By Kevin E. Noonan

A state appeals court in San Francisco upheld the California Institute for Regenerative Medicine (CIRM), the result of passage (by a referendum vote of 59% of California voters) of Proposition 71 in 2004.  The CIRM and California's legal capacity to fund the Institute under Proposition 71 were challenged by an alliance of anti-abortion and anti-tax groups, on the grounds that the program violated state laws limiting spending, and that Proposition 71 contravened ballot initiatives and conflicts of interest laws.

The appellate court unanimously ruled that Proposition 71 "suffers from no constitutional or other legal infirmity."  The court also noted that although the purpose of the Proposition was to fund research designed to find therapies "as speedily as possible," the litigation had "interfered with implementation for more than two years."

This decision, unless appealed to the California Supreme Court, will release a $3 billion research budget for stem cell research, and California will be able to both issue bonds to fund the research and distribute grant monies already awarded but awaiting this decision.  Nearly $45 million has already been spent on California universities and research institutes, but this money was either obtained from private philanthropists or through state loans.

Plaintiffs in the case were the People's Advocate and the National Tax Limitation Foundation, anti-tax groups, joined by the California Family Bioethics Council, which is affiliated with minister James C. Dobson's Focus on the Family.  Among the lawyers representing the plaintiffs was Dana Cody, executive director of the Life Legal Defense Foundation, an anti-abortion group.

The appellate court ruled that the program satisfied state law requiring governmental oversight, since a majority of the program's board was appointed by state officials and the program was subject to state audit.  The court also rejected challenges on technical requirements of voter propositions and conflict-of-interest rules.

Although further legal challenges are possible, it appears for now that California will be able to initiate the largest stem cell program in the nation, one that is serving as a model for other states.  Perhaps such efforts will stem the tide resulting from restrictive Federal government prohibitions and the Bush administration's ill-conceived stem cell policies, and prevent the U.S. from falling further behind the rest of the world in stem cell research.

Limitations on the Usefulness of Adult Stem Cells

    By Kevin E. Noonan

Five years ago, reports from the University of Minnesota promised to reconcile the budding science of human stem cell biology with the restrictive regulations the Bush administration had imposed on federally funded embryonic stem cell research.  These reports indicated that adult stem cells, specifically hematopoietic stem cells that are among the most plentiful and easily harvested, could be induced to grow into a variety of different tissues, including nerve, heart, lung, and liver tissue.

This early promise seems to have evaporated in the face of further research.  Indeed, a panel of scientific experts comprised of Minnesota faculty has concluded that the initial studies were "significantly flawed" and their conclusions incorrect.  The work was performed by Dr. Catherine Verfaillie when she was on the Minnesota faculty.  Although Dr. Verfaillie, now at the Catholic University of Leuven in Belgium, maintains that the basic conclusions of the work are sound (and there has been no allegations of misconduct), others are less sure.  And even Dr. Verfaillie acknowledges that there were flaws in how the early studies were performed.

These criticisms of the work are bolstered by the failure of others to replicate Dr. Verfaillie's results.  However, adult stem cells are notoriously difficult to work with, which would account for these negative results.  Dr. Verfaillie's reputation as an "impeccable" and "careful" scientist, according to Dr. Diane Krause of Yale University, have convinced many in the stem cell community that her work will ultimately be vindicated.

For now, however, the only reliable source of stem cells for a wide variety of different tissues are those derived from the inner cell mass of human embryos.  In the face of the continuing restrictions on federal funding for this research (President Bush having vetoed a bill that would have lifted these restrictions less than a year ago), states such as California and private entities such as Stanford University have mounted extensive efforts to fund embryonic stem cell research.  It is indisputable that the federal restrictions have retarded stem cell research in the U.S., driven scientists and technology overseas, and injured American competitiveness in this new biotechnology frontier.  These recent conclusions reduce the possibility that a politically safe "middle ground" may exist that could reverse some of these negative trends in a way acceptable to the more dogmatic of our political leaders and their constituencies.

Court Report

    By Sherri Oslick

A note to our readers:  Patent Docs apologizes to our readers for the recent Court Report hiatus.  This Court Reporter was deeply immersed in very intensive preliminary injunction proceedings and has just now been able to come up for air.  We will catch our readers up in the next few postings.  Patent Docs thanks our readers for their patience.

Purdue Pharma LP et. al. v. KV Pharmaceuticals Co. and Actavis Totowa LLC
1:07-cv-00032; filed January 16, 2007 in the District Court of Delaware

Infringement of U.S. Patent Nos. 5,508,042 ("Controlled Release Oxycodone Compositions," issued April 16, 1996), 5,549,912 (same title, issued August 27, 1996), and 5,656,295 (same title, issued August 12, 1997) following a paragraph IV certification as part of KV's and Actavis' filing of an ANDA to manufacture a generic version of Purdue Pharma's OxyContin® (controlled release oxycodone hydrochloride, used to treat pain).  View the complaint here.

Celgene Corp. v. Barr Laboratories, Inc. et. al.
2:07-cv-00286; filed January 18, 2007 in the District Court of New Jersey

Infringement of U.S. Patent Nos. 6,045,501 ("Methods for Delivering a Drug to a Patient While Preventing the Exposure of a Foetus or Other Contraindicated Individual to the Drug," issued April 4, 2000), 6,561,976 (same title, issued May 13, 2003), 6,315,720 ("Methods for Delivering a Drug to a Patient While Avoiding the Occurrence of an Adverse Side Effect Known or Suspected of Being Caused by the Drug," issued November 13, 2001), 6,561,977 ("Methods for Delivering a Drug to a Patient While Restricting Access to the Drug by Patients for Whom the Drug May be Contraindicated," issued May 13, 2003), 6,755,784 (same title, issued June 29, 2004), 6,869,399 (same title, issued March 22, 2005), and 7,141,018 (same title, issued November 28, 2006) following a paragraph IV certification as part of Barr's filing of an ANDA to manufacture a generic version of Celgene's Thalomid® (thalidomide, used to treat multiple myeloma and erythema nodosum leprosum).  View the complaint here.

Syngenta Biotechnology, Inc. et. al. v. DeKalb Genetics Corporation et. al.
1:07-cv-00038; filed January 19, 2007 in the District Court of Delaware

Declaratory judgment of invalidity and noninfringement of U.S. Patent No. 5,554,798 ("Fertile Glyphosate-Resistant Transgenic Corn Plants," issued September 10, 1996).  The '798 patent covers a genetically modified corn line exhibiting glyphosate resistance.  View the complaint here.

Monsanto Co. et. al. v. Jarrell
4:07-cv-00118; filed January 19, 2007 in the Eastern District of Missouri

Monsanto Co. et. al. v. Dorris
1:07-cv-00012; filed January 22, 2007 in the Eastern District of Missouri

The complaints in these two cases are quite comparable.  Infringement of U.S. Patent Nos. 5,352,605 ("Chimeric Genes for Transforming Plant Cells Using Viral Promoters," issued October 4, 1994) and RE39,247 ("Glyphosate-tolerant 5-enolpyruvylshikimate-3-phosphate Synthases," issued August 22, 2006) based on defendant's use of soybean seed produced from earlier planted Roundup Ready® soybean seed.  View the Jarrell complaint here.

Shire LLC v. Sandoz, Inc.
1:07-cv-00197; filed January 26, 2007 in the District Court of Colorado

Infringement of U.S. Patent Nos. 6,322,819 ("Oral pulsed dose drug delivery system," issued November 27, 2001) and 6,605,300 (same title, issued August 12, 2003) following a paragraph IV certification as part of Sandoz's filing of an ANDA to manufacture a generic version of Shire's Adderall XR® (a combination of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate, used to treat attention deficit hyperactivity disorder).  View the complaint here.

Sanofi-Aventis et. al. v. Watson Pharmaceuticals, Inc. et. al.
2:07-cv-00443; filed January 26, 2007 in the District Court of New Jersey

Infringement of U.S. Patent No. 6,514,531 ("Controlled-release Dosage Forms Comprising Zolpidem or a Salt Thereof," issued February 4, 2003) following a paragraph IV certification as part of Watson's filing of an ANDA to manufacture a generic version of Sanofi-Aventis' Ambien CR® (controlled release zolpidem tartrate, used to treat insomnia).  View the complaint here.

Narrowing the Scope of Continuation Applications

    By Kevin E. Noonan

Many have noted the recent trend in U.S. Supreme Court review, and disagreement with, Federal Circuit decisions.  Indeed, only two Federal Circuit decisions have been affirmed by the Supreme Court since 1995.  Some have questioned whether this level of negative review might tend to diminish the Federal Circuit's role in harmonizing U.S. patent law – the express purpose of Congress when the Federal Circuit was instituted in 1982.

On the other hand, the Supreme Court's recent increase in oversight on the Federal Circuit coincides with the criticism that the CAFC, far from harmonizing patent law, has no consistent philosophy amongst the judges, and that the result a litigant obtains depends more on the panel it draws than on the merits, legal and equitable, of its claims.  The recent decision in Hakim v. Canon Advent Group illustrates the problem.  This case involved a patent for a cup with a closure that prevented accidental spills but permitted liquid to be drawn from an opening in the cup when suction was applied by sipping.  One of the patents in suit recited broadly that the functional portion of the cup comprised an "opening" that was occluded when suction was not applied.  In an earlier parent case, the claim had read that the opening was a "slit," and the patentee distinguished the claims in that application from the cited prior art based on the presence of a slit.

That patent was not in suit, however.  The patent in suit was a continuation, and the patentee had explicitly put the Examiner on notice that the claims had been "broadened" when filing the claims reciting an "opening" rather than a "slit," although the patentee did not direct the Examiner's attention to this change as the basis for "broadening."  The patent was granted with no further objection by the Examiner.

The district court construed the term "opening" to require the opening be a slit.  The court held that "because Hakim did not retract any of his arguments distinguishing the prior art, he is held to the restrictive claim construction he argued during prosecution of the patent."  The inconsistency in this reasoning, of course, is that the patentee did not make these arguments during prosecution of the patent-in-suit; rather, these arguments were made in the parent application.  Before the Federal Circuit, Hakim argued that the district court erred, because by refiling his broader claims he had avoided any restriction on claim scope created by his arguments in the parent application.  Moreover, Hakim pointed out that he had affirmatively notified the Examiner that the claims in his continuation application were broader.  It is, Hakim argued, settled law that an Examiner is presumed to have performed his duties properly, and that by allowing the claims without further objection, he was entitled to a broader construction of the term "opening" than he had obtained in the narrower claims in his earlier patent.

Somewhat incredibly, the Federal Circuit affirmed.  In a unanimous decision authored by Judge Pauline Newman, the Court acknowledged that Hakim had the right to file a continuation with broader claims.  However, the Court then said that an applicant could not "recapture" claim scope that had been surrendered or disclaimed.  The Court affirmed the district court's finding that the Examiner had allowed the claims of the patent-in-suit "without further prosecution" based on the prosecution argument in the parent application.  The Court further acknowledged that an applicant had the right to rescind such surrender or disclaimer, but the panel held that an applicant must do more than Hakim had to evince the intention to rescind.

The flaw in the Federal Circuit's reasoning is that the case law cited in support of the proposition that an applicant could not recapture claim scope surrendered or disclaimed without a more explicit declaration of her intentions, all concerns prosecution of a single application.  In this context the rule makes sense, since an unscrupulous applicant could recapture claim scope late in prosecution that had been surrendered to overcome art asserted against her claims early in prosecution, and without the rule an examiner would be tasked with reviewing the entire prosecution history for every amendment made throughout prosecution.  The law reasonably places an affirmative duty on an applicant who wishes to recapture surrendered claim scope under these circumstances to inform the examiner with sufficient particularity that she understands the extent of the recaptured claim scope.

These considerations are, of course, non-existent when considering a continuation application.  It is well-established practice that claims of broader scope may be pursued in a continuation while claims of narrower scope grant as a patent.  The risks and consequences of this strategy have been highlighted in the Johnson & Johnston opinion, where the Court opined that claim scope disclosed but disclaimed (by accepting narrower claims) is "dedicated to the public," at least until a continuation having broader claims is obtained.  The Federal Circuit in Hakim appears to be expanding the scope of this doctrine even more broadly, where an applicant's right to pursue broader claim scope can depend on how or whether the applicant notifies the examiner of the continuation application of any narrowing amendments or arguments made in the parent case.

Hakim has serious implications for patent prosecution, particularly in the biotechnology arts.  Due to the complexity of the subject matter and the manner in which the Patent Office examines biotechnology patent applications, applicants frequently accept claims of narrower scope than filed and pursue the broader claims in continuation applications.  Hakim imposes a serious burden on applicants to assess all amendments and arguments made in a narrowly-issued parent application and identify all those that must be explicitly rescinded with notice provided to the Examiner.  The Hakim decision, however,  does not explicate the extent of the notice that would be sufficient to support rescission.  Unless Hakim requests, and the Court grants, reconsideration en banc, this decision has the capacity to make much mischief.  However, the Court has in the past shown the capacity to recognize, and correct, panel decisions that misstate the law (see Enzo Biochem, Inc. v. Gen-Probe Inc., 296 F.3d 1316 (Fed. Cir. 2002)).  We can only hope that the Court recognizes the errors in this decision and acts swiftly to correct them.

    Additional information regarding this case can be found at Patently-O.

Biotech Acquisitions Up, IPO's Down

    By Donald Zuhn

An article at BusinessWeek.com ("Biotech IPO's Iffy Prognosis") attributes a recent drop in initial public offerings (IPO's) for small biotech companies to the reluctance of investors to forgo big paydays as small biotechs use much of the cash raised from such offerings on drug development.  However, while the biotech IPO environment has become more cautious, the environment for biotech acquisitions has blossomed.  According to author Alex Halperin, the reason for this reversal of fortune is simple:  larger pharmaceutical companies have been more than willing to assume the risk associated with drug development and approval, and view the acquisition of newer biotech companies as an effective way to "outscource" their research.

In comparing two upcoming biotech IPO's for OncoGeneX and Rosetta Genomics with Merck's recent acquisitions of GlycoFi and Sirna Therapeutics and GlaxoSmithKline's purchase of Domantis, Halperin finds little in the IPO offerings to get enthused about.  Of course, the author's perception is likely colored by his characterization of OncoGeneX and Rosetta Genomics as "money-losing companies without an established product."  Ultimately, Halperin views acquisition as the more compelling alternative for small biotechs in the current business climate.

GenTel BioSciences Secures $2M in Funding

    By Mark Chael

GenTel BioSciences of Madison, Wisconsin recently announced that it had raised $1.5 million USD in angel financing for development and commercialization of protein chips and assays, plus $500,000 USD to be used to complete a new partnership with a large pharmaceutical company.  However, other than the fact that the deal has been signed, president and CEO Alex Vodenlich did not provide further details regarding the deal or the identity of GenTel's new partner.  Gentel had originally planned on raising only $1.5 million USD in the latest round of financing, however the partnership opportunity apparently required additional cash resources.

GenTel, also known as GenTel BioSurfaces or GenTel Corporation, is listed as the assignee on U.S. Patent No. 6,878,523 and three published U.S. patent applications, all of which disclose molecular interaction assays on solid surfaces, and in particular, transcription factor and signaling molecule interaction assays.

According to Gentel, the company currently offers "the most dependable protein microarray products for multiplex immunoassays."  Its proprietary PATH® ultra-thin nitrocellulose film surface chemistry "delivers the highest sensitivity for antibody microarray applications."  Additional information on Gentel, including its line of products and services, can be found here.

Court Report

    By Sherri Oslick

A note to our readers:  Patent Docs apologizes to our readers for the recent Court Report hiatus.  This Court Reporter was deeply immersed in very intensive preliminary injunction proceedings and has just now been able to come up for air.  We will catch our readers up in the next few postings.  Patent Docs thanks our readers for their patience.

Digene Corp. v. Third Wave Technologies, Inc.
3:07-cv-00022; filed January 11, 2007 in the Western District of Wisconsin

Infringement of U.S. Patent No. 5,643,715 ("Human Papillomavirus Type 52 DNA Sequences and Methods for Employing the Same," issued July 1, 1997) based on defendants' sale of its Invader® HPV A9 Oligo Mix.  View the complaint here, and a more in depth report here.

Pfizer Inc. et. al. v. IVAX Pharmaceuticals, Inc.
2:07-cv-00174; filed January 11, 2007 in the District Court of New Jersey

Infringement of U.S. Patent No. 5,382,600 ("3,3-Diphenylpropylamines and Pharmaceutical Compositions Thereof, issued January 17, 1995) following a paragraph IV certification as part of IVAX's filing of an ANDA to manufacture a generic version of Pfizer's Detrol® (tolterodine tartrate, used to treat overactive bladder).  View the complaint here.

Teva Pharmacuetical Industries Ltd. et. al. v. Torrent Pharmaceuticals Ltd. et. al.
1:07-cv-00024; filed January 12, 2007 in the District Court of Delaware

Teva Pharmaceutical Industries Ltd. et. al. v Hetero Drugs Ltd.
1:07-cv-00122; filed January 12, 2007 in the District Court of Maryland

Teva Pharmacuetical Industries Ltd. et. al. v. Cipla Ltd. et. al.
2:07-cv-00240; filed January 12, 2007 in the District Court of New Jersey

Teva Pharmacuetical Industries Ltd. et. al. v. Hetero Drugs Ltd.
2:07-cv-00241; filed January 12, 2007 in the District Court of New Jersey

Teva Pharmaceutical Industries Ltd. et al v. Cipla Ltd. et al.
1:07-cv-00316; filed January 12, 2007 in the Southern District of New York

Teva Pharmacuetical Industries Ltd. et. al. v. Matrix Laboratories Ltd. et. al.
2 :07-cv-00581; filed February 2, 2007 in the District Court of New Jersey

The complaints in these cases are substantially identical.  Declaratory judgment of infringement of U.S. Patent Nos. 6,600,073 ("Methods for Preparation of Sertraline Hydrochloride Polymorphs," issued July 29, 2003), 6,500,987 ("Sertraline Hydrochloride Polymorphs," issued December 31, 2002), 6,495,721 ("Sertraline Hydrochloride Form II and Methods for the Preparation Thereof," issued December 17, 2002), and 6,897,340 ("Processes for Preparation of Polymorphic Form II of Sertraline Hydrochloride," issued May 24, 2005), all directed to methods of manufacturing crystalline forms of sertraline hydrochloride (the API in Zoloft®, used to treat depression), based on the defendants' filing of a DMF (drug master file) with the FDA.  View the Torrent complaint here.  (The Torrent case was voluntarily dismissed by Teva without prejudice on February 15.)

Teva Pharmaceuticals Industries Ltd. et. al. v. Lupin Limited et. al.
1:07-cv-00121; filed January 12, 2007 in the District Court of Maryland

Teva Pharmacuetical Industries Ltd. et. al. v. Zydus-Cadila Healthcare et. al.
2:07-cv-00242; filed January 12, 2007 in the District Court of New Jersey

Teva Pharmacuetical Industries Ltd. et. al. v. Sandoz Inc.
2:07-cv-00243; filed January 12, 2007 in the District Court of New Jersey

Teva Pharmacuetical Industries Ltd. et. al. v. Andrx Corp.
2:07-cv-00244; filed January 12, 2007 in the District Court of New Jersey

Teva Pharmacuetical Industries Ltd. et. al. v. Genpharm Inc.
2:07-cv-00245; filed January 12, 2007 in the District Court of New Jersey

Teva Pharmacuetical Industries Ltd. et. al. v. InvaGen Pharmaceuticals Inc. et. al.
2:07-cv-00246; filed January 12, 2007 in the District Court of New Jersey

Teva Pharmacuetical Industries Ltd. et. al. v. Lupin Limited et. al.
2:07-cv-00247; filed January 12, 2007 in the District Court of New Jersey

Teva Pharmacuetical Industries Ltd. et. al. v. Apotex Inc. et. al.
2:07-cv-00248; filed January 12, 2007 in the District Court of New Jersey

Teva Pharmaceutical Industries Ltd. et al v. InvaGen Pharmaceuticals Inc. et. al.
1:07-cv-00315; filed January 12, 2007 in the Southern District of New York

The complaints in these cases are substantially identical.  Declaratory judgment of validity and infringement of U.S. Patent Nos. 6,600,073 ("Methods for Preparation of Sertraline Hydrochloride Polymorphs," issued July 29, 2003), 6,500,987 ("Sertraline Hydrochloride Polymorphs," issued December 31, 2002), 6,495,721 ("Sertraline Hydrochloride Form II and Methods for the Preparation Thereof," issued December 17, 2002), and 6,897,340 ("Processes for Preparation of Polymorphic Form II of Sertraline Hydrochloride," issued May 24, 2005), all directed to methods of manufacturing crystalline forms of sertraline hydrochloride (the API in Pfizer's Zoloft®, used to treat depression) based on defendants' anticipated sale of generic Zoloft® following final FDA approval of defendants' ANDA (at the end of Teva's exclusivity period).  View the Lupin complaint here.  (The Zydus and Genpharm cases were voluntarily dismissed by Teva without prejudice on February 22.)

Nature's Unpredictable Thesaurus

    By Kevin E. Noonan

DNA has a unique status among biological molecules, being both a chemical and information comprising the nucleotide sequence that encodes the amino acid sequence of a gene's cognate protein.  In a recent article in Science, Michael Gottesman and his colleagues at the National Institutes of Health have demonstrated that even this straightforward understanding of information flow involved in gene expression may be more complicated than it has appeared.  These results have implications not only for understanding the underlying biology but in protecting genes with patents.

The genetic code is degenerate, meaning that the number of possible triplet codons (64) is greater than the number of amino acids (20) corresponding to these codons.  This fundamental concept in molecular biology was first postulated by Francis Crick and verified by Marshall Nirenberg and others in the '50's and '60's.  The physical embodiment of the degeneracy of the code is transfer RNA (tRNA), small RNA molecules having a triplet codon at one "end" of the molecule and a position at the other end to which the corresponding amino acid is linked; the specificity resides in the "charging" enzymes that match tRNA to its proper amino acid.  Most amino acids are encoded by more than one triplet and have more than one tRNA charged with that amino acid.  Leucine has the most (with 6) and methionine and tryptophan are the exceptions that have only one cognate tRNA.

It is known that not all tRNAs for a particular amino acid are produced in the same abundance, either in cells of a particular species or between species.  Thus, early genetic engineering efforts for some proteins involved changing codon choice for DNA from one species (human) for expression in other species (bacteria and yeast).  The underlying assumption, however, is that there was no difference between these codons other than tRNA abundance, and that an amino acid sequence could be encoded by any one of a number of nucleotide sequences representing "synonyms" of the native sequence.

Gottesman's work changes all that.  His team looked at the gene encoding human MDR1, a plasma membrane, ATP-dependent transporter that recognizes and transports from the cell many structurally-different chemical compounds.  This protein, termed P-gp, is responsible for protecting colon, kidney, and other cells from environmental toxins; forms a part of the blood-brain barrier; and makes certain cancer cells resistant to chemotherapeutic drugs.  Gottesman expressed two different embodiments of the MDR1 gene, where a certain portion of the amino acid sequences of each were encoded by a synonymous stretch of nucleotides.  In this portion of the gene, the encoded amino acid sequence was the same but the codons used in the two embodiments were different:  one of them used rare triplet codons and the other did not.  His results were startling:  not only were the proteins produced at different rates (which could be expected if the rare codon-containing species was translated more slowly), but the phenotype of the two proteins differed as well.  For example, the rare codon-encoding embodiment showed different sensitivity to certain inhibitors.  In addition, the different forms showed different susceptibility to proteolytic enzymes and different binding characteristics with conformation-specific antibodies.  Gottesman interpreted these results to mean that differences in translation speed or efficiency could change the way the protein was folded as it was produced at the ribosome, and the differences in protein folding caused (or at least contributed to) the observed phenotypic differences.

It is unknown how common it is to have these kinds of phenotypic differences result from triplet codon synonyms.  P-pg differs from many other proteins in significant ways.  For example, it is relatively nonspecific in substrate recognition, being able to transport many structurally-different compounds across the cell's plasma membrane against a concentration gradient.  Other researchers have found changes in substrate specificity associated with mutations in the amino acid sequence (see Choi et al., 1988, Cell 53:519-29 and Safa et al., 1990, Proc. Natl. Acad. Sci. U.S.A. 87:7225-29).  The protein is also internally-duplicated, and other members of the MDR gene family are involved in dramatically different phenotypes despite having very similar primary amino acid sequences (see Van der Bliek et al., 1987, EMBO J. 6:3325-31 and Smith et al., 1994, FEBS Lett. 354:263-66).

Gottesman's findings have implications for how patent protection is obtained for genes.  Heretofore, it has been common to recite a gene claim in the form of "an isolated nucleic acid encoding a protein having an amino acid sequence identified by SEQ ID NO: X."  This claim is typically supported by one cloned or otherwise identified sequence, and encompasses all nucleotide sequences encoding the amino acid sequence.  Said another way, the claim encompasses all nucleotide sequence synonyms of the encoded amino acid sequence.  When these synonymous sequences were believed to be equivalent (i.e., to encode the same protein with the same phenotypic characteristics), there was no reason not to consider elucidation of the nucleotide sequence and translation into the predicted amino acid sequence as encompassing all these synonymous sequences.  If the effect of synonymous sequences detected by Gottesman is widespread, however, it may be more appropriate to permit patenting of claims to specific synonymous sequences, provided that they are associated with a phenotype that differs in some way from the phenotype of the protein encoded by the patented sequence.  This would be the equivalent of patenting a chemical species encompassed within a prior art genus, where the species has unexpected or unappreciated properties that distinguish it from the properties of the generic compounds.  These results also illustrate one other example of how the human genome has evolved to maximize genetic variability and helps explain the general observation from the Human Genome Project, that there are many fewer human genes than were expected to be found.

Conference & CLE Calendar

February 27-28, 2007 - Patent Portfolio Management (American Conference Institute) - New York, NY

March 21-22, 2007 - Complex IP & Technology Transactions Conference (Law Seminars International) - Chicago, IL

March 25-29, 2007 - American Chemical Society National Meeting - Chicago, IL

April 16-18, 2007 - Biotechnology: Patent Prosecution, Licensing, Litigation & Hatch-Waxman (Patent Resources Group) - Orlando, FL

April 27, 2007 - Patent Claim Construction Workshop (Law Seminars International) - Atlanta, GA

May 6-9, 2007 - BIO International Convention - Boston, MA

Retinal Specialist on the Avastin®/Lucentis® Controversy

    By Kevin E. Noonan

Earlier this week, the National Eye Institutes (NEI) of the National Institutes of Health announced that it would conduct a study comparing the effectiveness of two Genentech drugs, Lucentis® and Avastin®, for the treatment of age-related macular degeneration (AMD).  This was not good news for Genentech, because although treating AMD with Avastin® is an off-label use (Avastin® is approved for treating colon and certain lung cancers), the cost of the treatment is between 1% and 3% of the cost of Lucentis® treatment ($20-60 per dose versus $2,000/dose).

Lucentis® has been a great success for Genentech despite its cost, because it is one of only two FDA approved drugs for treating neovascular or "wet" AMD, a condition that if untreated leads inexorably to blindness.  The drug has been so successful that it has the lion's share of the market over Macugen (sold by EyeTech).  The drug has not been without controversy, however, since it is not a cure for AMD but merely stablizes the wet form, and in many patients prevents the condition from worsening.  This means that the drug must be administered like insulin or other maintenance drugs.  At a cost of $2,000/dose and a once-a-month dosing schedule, the cost to treat the half-million "wet" AMD patients in the U.S. is greater than $10 billion per year.  According to Dr. Edward Chaum, Plough Foundation Professor of Ophthalmology, University of Tennessee, this is more than the entire Medicare budget for all of ophthalmology (cataracts, diabetes, glaucoma, and everything else) combined.

Avastin® is so much cheaper because it is priced at $600/vial for intravenous use, but is injected into the eye at such small doses (0.1cc) that each vial can deliver 30 doses ($20/dose), says Dr. Chaum.  Genentech has opposed the off-label use of Avastin®, and cautioned ophthalmologists that there is a greater risk of stroke using Avastin.  However, the increased stroke risk was seen at the therapeutic dose for cancer patients, which is 400-fold higher than the dose used to treat AMD.  Recently, Genentech also reported that certain doses of Lucentis used for AMD are also associated with an increased risk of stroke.

Not surprisingly, Genentech's behavior has angered the Retina ophthalmology community, which has generally ignored Genentech's warnings and has been widely using Avastin® for AMD.  The results of the NEI study will not be available for about a year, but the situation should be clarified sooner than that, in view of anecdotal evidence from such off-label use and the expected disclosure of preliminary results.

Dr. Chaum and others believe that the results of the head-to-head clinical trial will likely validate use of Avastin® as being at least equivalent to Lucentis®.  If confirmed, Genentech will be forced to choose between removing Avastin® from the marketplace (which is unlikely, since it is a $2 billion/ year drug for cancer indications), or acquiescing to providing the drug in the lower dose amounts that are now provided only by compounding pharmacies.

The hard reality is that AMD is a progressive disease whose best treatment is prevention.  It is an indication of the dire consequences of AMD (blindness in old age) that patients and their physicians endure the therapeutic regimen (direct injection into the eye every 4-6 weeks) for drugs that at best only slow disease progression.  Genentech lost an opportunity with Avastin® and Lucentis® to solidify ties with a large and growing patient population and their doctors.  Perhaps their cooperation, if forthcoming, in the face of the expected equivalence results for these two drugs, and the resulting greater affordability for the majority of patients, can repair the damage.

Lower Doses of Genentech's Avastin® Effective in Treating Lung Cancer

    By Kevin E. Noonan

The news keeps getting worse for Genentech.  On the heels of the announcement that the National Institutes of Health would fund a study comparing the efficacy of Lucentis® and Avastin® (see "Retinal Specialist on the Avastin®/Lucentis® Controversy"), Genentech disclosed the results of an Avastin® study done by its parent company, Roche Holdings Ltd. of Switzerland.  In this study, Avastin® treatment was shown to be just as effective in lung cancer patients using half the recommended dose as it is with the full dose.  Treating with half the recommended dose would drop the cost, and hence Genentech's revenues, from $8,800/month to $4,400/month, threatening a franchise worth about $3 million yearly (a number expected to grow as the U.S. population continues to age).

The only silver lining is that the Roche study did not present evidence on the effects of the lower dose on long-term survival.  Although patients treated in the study with the lower dose showed not difference in mortality, the length of the study was insufficient to establish no difference over a longer timeframe.  Thus, low dosing comprises a risk for cancer patients, which may inhibit the 75% of oncologists who have not switched to the lower dose from doing so.  In any event, this study continues to threaten Genentech's newfound dominance as the market leader in U.S. biotechnology companies.

National Institutes of Health Announce Influenza Gene Database

    By Kevin E. Noonan

The U.S. National Institutes of Health (NIH) announced Wednesday that it had assembled a database of the entire genomic complement of 2,000 human and avian influenza strains that are publicly available from the National Institute of Allergy and Infectious Diseases (NIAID).  The information in this database represents flu samples collected worldwide.

The database is the result of the Influenza Genome Sequencing project, started at NIH in 2004.  NIAID funded a variety of influenza sequencing efforts by university and private entities, including The Institute for Genomic Research (TIGR); Wadsworth Center of the New York State Department of Health in Albany, NY; the Centers for Disease Control and Prevention in Atlanta; St. Jude Children's Research Hospital in Memphis, TN; the World Organization for Animal Health / Food and Agriculture Organization of the United Nations (OIE/FAO) Reference Laboratory for Newcastle Disease and Avian Influenza in Padova, Italy; The Ohio State University in Columbus, OH; Children's Hospital Boston; Baylor College of Medicine in Houston; and Canterbury Health Laboratories in Christchurch, New Zealand.

The work is not completed:  sequencing capacities have grown to more than 200 viral genomes per month and is ongoing.  The sequence information is being posted on the GenBank database as it is acquired.

This continued effort is relevant to developing vaccines for influenza, which is characterized by high mutation and recombination rates.  This information is particularly useful for developing vaccines to so-called "seasonal" influenza, which kills between 250,000 and 500,000 people worldwide each year.  The information also helps determine the appropriate vaccines for the population of influenza virus extant each season and in different parts of the world.  The database will be even more important if a pandemic strain arises, such as the Asian "bird flu" of recent years, since pandemics can cause much more widespread mortality - an estimated 40-60 million people died in the 1918 pandemic.

Final Office Action Issued in Reexamination of Cabilly Patent

    By Donald Zuhn

Genentech, Inc. announced on Wednesday that the USPTO has issued a final Office Action in its reexamination of U.S. Patent No. 6,331,415, rejecting the claims of what is generally referred to as the Cabilly patent. In its press release, Genentech stated its intention to respond to the final Office Action and, if necessary, appeal the decision through "all appropriate means of review within the Patent Office and the courts."

The '415 patent was the subject of a recent Supreme Court decision, in which the Court found that patent licensee Medimmune could challenge the validity of the patent while continuing to pay patent royalties under the license, and that such a suit fulfilled the "cases or controversies" requirement of Article III of the Constitution (see "Medimmune, Inc. v. Genentech, Inc. (2007)").

Genentech noted that despite the USPTO's determination, the '415 patent will remain "valid and enforceable" throughout the appeals process, which Genentech estimated would take at least one or two years.

In Defense of Patents (And Even Their "Trolls")

     By Kevin Noonan

It isn't often that you hear someone defend so-called "patent trolls."  With the exception of publications directed towards the patent bar, most mainstream media are content to parrot the idea that anyone (other than a large manufacturing company) who asserts its patents in court is merely a "troll" trying to achieve the technological equivalent of a mugging.

Which is why an OpEd piece in none other than the February 21, 2007 issue of The Wall Street Journal is a refreshing bit of common sense.  Written by Laura Peters, general counsel of Immersion Corp., the piece is directed towards Congressional attempts to "reform" the patent system.  As readers of this space will appreciate, some of the proposed cures are worse than the purported disease, and Ms. Peters goes after two of them.

The first is the idea – made current by Federal Circuit Judge Kimberley Moore when Judge Moore was an academic – that patent continuation applications are somehow an improper attempt to "game" the patent system and obtain undeserved patents.  Despite being supported by questionable statistics (which run contrary to many a practitioner's experience with the Patent Office bureaucracy), this idea motivated proposed rules changes last year that would have limited continuation application filings.  The intellectual property community responded so negatively that the proposed rules are (thankfully) no longer imminent (see "Patent Applicants Beware: The Rules Are Changing (Again)" Part 1 and Part 2).

Ms. Peters points out the practical reasons why such proposals are wrongheaded.  These include the fact that continuation applications are important, particularly to small companies with emerging technologies.  She cites the costs of preparing many (rather than one) patent applications to cover all aspects of a new technology, and the practical reality that some aspects of the technology are underappreciated at the time the first patent application is filed but before the technology is fully developed.  She points out that the consequence of restricting continuation practice would be to give a boon to the copyists, who could use the disclosed but unclaimed subject matter without fear of patent infringement liability, greatly reducing the technology's value.

Ms. Peters is also a skeptic about the U.S. adopting a European-style "opposition proceeding," seeing this as a way for large companies (with greater resources) to harass small companies without the attendant risk of infringement liability.  She identifies the real beneficiaries of the "cheaper, faster" alternatives to litigation:  large companies who do not need these advantages, and the losers:  small companies who face the increased cost of defending against opponents.  According to Ms. Peters, even without such opposition proceedings, small companies are forced to fight on two fronts, as accused infringers can use existing re-examination proceedings in concert with patent infringement litigation.

The real problem with all these proposals is that they increase the cost of patenting, and the extra burden falls most heavily on those companies least able to afford them:  small, innovative start-ups.  These are the companies that need to use their funds to invest in bringing their products to market.  Without them, Ms. Peters notes, innovation will be the purview only of large companies with big budgets.

And we will be the losers.  Taking as her examples Steve Jobs, Don Hewlett, and Andre Pavel, she reminds us that there is a reason (at least in America) that so many of our cutting-edge, groundbreaking technologies come from basement workshops and garages:  large companies lack the flexibility to pursue innovation with the same vigor as smaller ones.  It is these smaller companies that have transformed this country from the tired, aging rust-belt has-been of the 1980's to the economic lion it was at the turn of the century.  And the U.S. patent system and ability to protect all this innovation with patents made this turnaround possible.  We should be wary of misguided attempts to fix apocryphal problems, or the next time we might not be so lucky.