By Kevin E. Noonan --
The Wisconsin Alumni Research Foundation (WARF) has now responded to the U.S. Patent and Trademark Office's rejections of its stem cell patents in reexamination. These patents, U.S. Patent Nos. 5,843,780 (claiming primate embryonic stem (pES) cells); 6,200,806 (claiming human embryonic stem cell (hES) cells); and 7,029,913 (hES) (collectively, the Thomson patents) were challenged in a re-examination petition filed July 17, 2006 and granted by the U.S. Patent and Trademark Office on September 29, 2006. The '708 and '806 patents are undergoing re-examination under the conventional (35 U.S.C. § 302-307) ex parte re-examination proceedings (under Serial Nos. 90/008102 and 90/008139, respectively), while the '913 patent is being re-examined inter partes (35 U.S.C. § 311-318), a more recent procedure that permits significantly more participation by a third party re-examination requestor (under Serial No. 95/000154).
Earlier this year the Patent Office rejected all the claims in all the patents in all the re-examinations. These rejections were based on two prior art patents to Hogan (U.S. Patent Nos. 5,453,357 and 5,690,926) that formed the basis for rejection under 35 U.S.C. §§ 102 (anticipation) and 103 (obviousness). The Actions assert that the Hogan patents disclose human embryonic stem cells, although they acknowledge that the methods for producing these cells are different from the Thomson methods. The Actions also asserted a rejection based on U.S. Patent No. 5,166,065 to Williams, which the Office asserted disclosed both human stem cells and methods for making them that are "identical" to the Thomson methods. These anticipation rejections are all based on the prior art cells "inherently" possessing the properties of "true" embryonic stem cells, as defined in the Thomson patents. Finally, the Action rejected WARF's claims on anticipation and obviousness grounds of the teachings of a scientific journal article reference by Bongso (see "It's Time to Stop the Hypocrisy over Stem Cell Patents - Part I"), as well as asserting additional obviousness rejections over a combination of these references and additional secondary prior art.
In responding, WARF amended Claim 1 of the '608 patent, directed to human ES cells themselves, to recite that the claimed human ES cells were "derived from a preimplantation embryo." Claim 9, directed to a method for producing human ES cells, was amended to recite that the cells "produced" by the method were "capable of proliferation as undifferentiated cells for more than one year" (a limitation contained - although worded differently - in Claim 1 as originally granted). Also added were new claims:
12. A method of isolating a pluripotent human embryonic stem cell line, the method comprising the steps of:
(a) isolating a human blastocyst;
(b) isolating cells from the inner cell mass of the blastocyst of (a);
(c) plating the inner cell mass cells on embryonic fibroblasts, wherein inner cell mass-derived cells masses are formed;
(d) dissociating the mass into dissociated cells;
(e) replating the dissociated cells on embryonic feeder cells;
(f) selecting colonies that have compact morphologies that are flatter than mouse embryonic stem cell colonies, wherein the cells have high nucleus to cytoplasm ratios and prominent nucleoli;
(g) culturing the cells of the selected colonies to produce an isolated human embryonic stem cell line that is capable of proliferation as undifferentiated cells for more than one year.13. A method as claimed in claim 23, further comprising maintaining the isolated cells on a fibroblast feeder later to prevent differentiation.
14. A cell line that is capable of proliferating for one year as undifferentiated cells developed by the method of claim 12.
In their Remarks, the patentees distinguished the prior art (mouse embryonic stem cells and human embryonic germ cells) on the basis of biomarker expression, cell source, and biological function and capacities. The anticipation rejections were countered by argument, contending that the art did not inherently anticipate because the art did not disclose human ES cells, and that the Williams reference did not contain the teachings ascribed to it by the Examiner. In addition, not unexpectedly, WARF argued that the cited references did not anticipate because they did not enable WARF's claimed human ES cells. This argument was supported by the position, taken during prosecution of the Williams patent by the Patent Office, that the Williams' specification enabled nothing more than mouse ES cells. The argument was also supported, perhaps more forcefully, by the assertion that human ES cells cultured as described by Williams (without a feeder layer and in culture media supplemented with leukemia inhibitory factor) would not proliferate but rather would differentiate.
WARF further argued that, although mouse ES cells and human embryonic germ cells were known, as were methods for making these cells, application of these methods was not reliable, and isolation of human ES cells from pre-implantation embryos was unpredictable. WARF also set forth the several differences in biological properties of the claimed cells over the cells of the cited art. Also mentioned was the long history of failure of others to use the methods known in the art and developed with mouse ES cells to produce human ES cells. WARF also provided a number of exhibits illustrating the widespread acclaim Dr. Thomson had enjoyed as a result of his invention. Importantly, WARF's response was couched in the language of KSR International Co. v. Teleflex Inc. and Graham v. John Deere Co., and emphasized the unpredictability in the biotechnological arts that distinguish them from the simple mechanical subject matter of the Teleflex patent as well as the secondary indicia of non-obviousness (long-felt need, failure of others, recognition and acceptance in the art, and commercial success).
With regard to the Hogan reference, WARF argued the biological differences (in source, biomarker expression, and differentiation potential) between human EG cells and human ES cells, and the admissions and characterizations of the Hogan cells made by Hogan herself in her patent specification and during prosecution of her patents.
WARF distinguished its claims over the Bongso reference by relying on the differences in proliferative capacity (said difference being made an explicit limitation by WARF's amendments): the Bongso cells were incapable of proliferating for more than two or so cell divisions, in contrast to the Thomson cells that were required by the amended claims to be capable of proliferating as undifferentiated cells for at least one year. This distinction was supported by statements made by Bongso in his subsequent scientific publications.
Finally, WARF distinguished its claims from a combination of a variety of references relating to ES cells from other mammals with arguments similar to those made in response to rejections based on the Hogan and Williams patents: none of the references taught human ES cells, and the methods used were too unpredictable to render obvious Dr. Thomson's production of these cells.
WARF's arguments were buttressed by a Declaration under Patent Office Rule 132 by Dr. Colin Stewart, a mouse embryologist having an appointment at the Institute of Medical Biology in Singapore. Dr. Stewart, whose vita demonstrates expertise in mouse ES cells, attested that even among mouse strains there was variability in the facility with which ES cells could be isolated (i.e., some strains reliably produced ES cells, and some strains did not, and success was not predictable a priori). Dr. Stewart also averred that attempts to isolate rat or ovine ES cells had been unsuccessful. Dr. Stewart's declaration also supported WARF's arguments made with regard to the limitations of the prior art. In addition, Dr. Stewart affirmed the long history of failure of others and the astounding acclaim earned by Dr. Thomson for his invention.
Similar amendments and arguments were made for the '780 patent and in the inter partes re-examination of the '913 patent, each of which was also supported by a Declaration from Dr. Stewart. The third-party requestors will have an opportunity to address WARF's arguments (in the inter partes reexamination) in a submission due in the Patent Office in about a month. Under the "special dispatch" rules for patent re-examinations, it can be expected that any further Action should issue from the Patent Office by autumn, and that a final (appealable) determination should issue by the end of this year.
For additional information on this and related topics, please see:
- "It's Time to Stop the Hypocrisy over Stem Cell Patents - Part II," April 26, 2007
- "It's Time to Stop the Hypocrisy over Stem Cell Patents - Part I," April 17, 2007
- "WARF Stem Cell Patent Claims Rejected in Re-examination," April 3, 2007
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