By Kevin E. Noonan --
Biologic drugs, the pharmaceutical embodiments of biotechnology, are an important part of the current pharmaceutical armamentarium, and this is only expected to increase. There are 150 approved biologic drugs in the U.S., contributing $40 billion to U.S. drug costs in 2005; these costs are expected to increase to $90 billion by 2009. Thus, they have become a target for legislation to reduce the costs by promoting generic (more properly, follow-on) drugs at (presumably) reduced costs.
Biologic drugs are generally peptides and proteins, particularly monoclonal antibodies, but can also include vaccines. Currently-available biologic drugs include Humulin® (recombinant human insulin); Epogen® (recombinant human erythropoietin); Herceptin® (anti-Her2/neu monoclonal antibody); beta-interferon (for treating multiple sclerosis); Cerezyme® (for treating Gaucher's disease); Enbrel® (soluble TNF receptor); and Gleevac® (anticancer monoclonal antibody). The average costs of biologic drug treatment is about $72,000/year (compared to about $1,000 for conventional "small molecule" pharmaceuticals). Part of the difference in costs reflects the difficulties in bringing these drugs to market. And some of these differences in costs has to do with the increase complexity of biologic drugs and the methods by which they are produced.
Conventional "small molecule" drugs typically comprise about 20-100 atoms (for example, omeprazole, the active ingredient in Prilosec®, contains 42 atoms), while biologic drugs comprise 5,000 to 50,000 atoms. Moreover, peptide and protein embodiments (including monoclonal antibodies) are complex polymeric chains that can adopt secondary and tertiary structure beyond their simple linear formulae. In addition, biologic drugs can be heterogeneous: besides the protein components, biologic drugs can comprise carbohydrates (by glycosylation), lipids and occasionally small molecule cofactors. This chemical heterogeneity also complicates formulation of biologic drugs, wherein excipients and other components must be compatible with the physicochemical differences between biologic drug components.
Biologic drugs are regulated under the Public Health Service Act (rather than the Food, Drug and Cosmetic Act), because the first biologic drugs to be regulated were vaccines in the early Twentieth century. Although administered by the Food and Drug Administration (specifically, the Center for Biologics Evaluation and Research), approval for biologic drugs is sought by submitting a Biologics Licensing Application (BLAs), rather than a New Drug Application. Legislation directed towards facilitating approval of "follow-on" biologic drugs seek to amend the section of the PHSA concerning BLAs. There have been three bills introduced in Congress relating to follow-on biologics: H.R. 1038, the "Access to Life-saving Medicine Act" (introduced by Congressman Waxman); H.R. 1956, the "Patient Protection and Innovative Biologics Medicines Act" (introduced by Congressman Inslee); and H.R. 5629, the "Pathway for Biosimilars Act" (introduced by Congresswoman Eshoo). None of these bills have been acted upon, in the face of intensive lobbying from both sides of the "follow-on" debate.
The bills are different, but have in common leaving with FDA the responsibility to approve follow-on biologic drugs that are "comparable" or "biosimilar" to the innovator biologic drug. The bills also share the goal of requiring follow-on biologic drugs to show "comparability" or "biosimilarity" prior to approval, coupled with post-approval surveillance. They also each provide for some amount of market and data exclusivity for the innovator.
The bills differ in the requirements for showing biosimilarity. The Waxman bill provides a number of different types of evidence that can be required to establish such similarity, but also contains provisions that would permit a wider range of differences between the follow-on and the innovator drug (including amino acid sequence variants). The Inslee bill entrusts the Secretary of Health and Human Services with substantially more discretion as to the requirements for biosimilarity on a case-by-case basis, coupled with a requirement that the Secretary promulgate "guidances" for its criteria that are subject to public comment. The Eshoo bill is some ways is a compromise, having a regime of analytical testing, animal experiments, and human clinical trials for gaining approval, but giving the Secretary the discretion to waive the requirements on a case-by-case basis (limited, as with the Inslee bill, by published guidances that have been subjected to public comment).
The scientific issue behind the concern for biosimilarity is the capacity for a follow-on biologic to be equivalent to the innovator drug; actually, the concern is how difficult it may be to make such a follow-on biologic drug. The innovators maintain that it is virtually impossible to make a true "generic" biologic, due in part to how such drugs are made. Unlike conventional pharmaceuticals that are made using well-defined and controlled chemical reactions, biologic drugs are almost always made by a living cell (bacterial, yeast, or mammalian), and the cells used by the innovators are rarely available. Cells, even cells of the same type, are expected to have phenotypic variability that can influence the structure of the biologic drug product made by them. These differences can include differences in primary amino acid sequence (although this type of variability should be rare, in view of the possibility for significant changes in the biologic properties of such variants). The differences are more likely to be in post-translational processing, particularly in glycosylation patterns that are known to differ between different cell types (and may even differ between different strains or populations of the same cell type). It can also be expected that different formulations may have different properties. Potential consequences of this type of variability include changes in biovailability, biological activity, solubility (including the propensity for agglomerization), and immunogenicity.
These are not merely theoretical problems. In one instance, changing the cell line used to produce the experimental biologic CNT085 resulted in changed pharmacokinetics of the drug. An innovator's new production facility (expressly designed to minimize differences in the production protocol) produced drug product that had 40% lower drug levels in patients' blood. Changing formulation to reduce detergent levels led to an increase in microclumping that affected bioavailability. And in perhaps the most significant event, administration of a recombinant blood cell growth factor produced an immunological response that not only inhibited bioactivity of the recombinant but also the endogenous species of the factor.
These occurrences support the position of innovator biologics companies and their representatives (such as the Biotechnology Industry Organization, see "BIO CEO Provides Update on Patent Reform and Follow-on Biologics Legislation - Part II") to insist that public safety requires human clinical trials to establish the safety and efficacy of follow-on biologic drugs, with strict post-approval surveillance. The "generic" biologics industry opposes these strict requirements, maintaining that the requirements should be tailored to fit the particular biologic drug and to give FDA the flexibility needed to make such a determination on a case-by-case basis. Other factors in dispute involve the increased barriers to entry occasioned by requiring human clinical trials, in both time and expense, as well as the ethical difficulties in requiring human clinical trials that may not be necessary (although the necessity vel non of such trials will only be known after the fact).
Patents and the requirements for patentability must be considered in this climate. There are no more stringent requirements for patentability for biologic drugs (more properly, pharmaceutical composition claims comprising a biologic compound) than for conventional drugs, nor does U.S. patent law require disclosure of clinical trials or safety and efficacy data for pharmaceutical composition claims. However, the extent of disclosure required for a claim depends on claim scope, since 35 U.S.C. § 112, first paragraph, has been interpreted to require disclosure of how to make and use an invention throughout the full scope of the claim. It is not unreasonable to expect that pharmaceutical composition claims will be required to be supported by disclosure that would enable one of ordinary skill in the art to produce a useful biologic drug (see In re Wands, 858 F.2d 731 (Fed. Cir. 1988)). Indeed, the trial court in Amgen Inc. v. Hoechst Marion Roussel, Inc. disqualified prior art (that also must satisfy an enablement requirement) relating to purification of human urinary erythropoietin based on testimony that the method did not yield uEPO in sufficient quantities or purity to have a biological effect. And the Federal Circuit has shown a penchant recently to give significantly closer scrutiny to the correspondence between claim scope and disclosure. Examples include:
• Pharmaceutical Res. Inc. v. Roxane Labs, Inc., where the patent was invalidated on non-enablement grounds for claiming formulations of megastrol acetate with a flocculating agent, supported by disclosure of only three flocculating agents;
• Monsanto Co. v. Syngenta Seeds Inc., invalidating a patent to methods for transforming "plant cells" in view of uncontroverted testimony that at the time the application was filed the art recognized methods for transforming dicotyledenous but not monocotyledonous plants;
• Sitrick v. DreamWorks, LLC, where a patent directed to methods for adding voice-overs to video did not enable overdubbing methods used by defendants;
• Automotive Tech. Int'l, Inc. v. BMW of North America, Inc., invalidating a patent that disclosed mechanical airbag sensors but claimed both mechanical and electronic sensors;
• Liebel-Flarsheim Co. v. Medrad, Inc., where disclosure of jacketed needle holders did not enable claims to unjacketed needle holders.
This trend, part of more than a decade of Federal Circuit jurisprudence in areas such as the written description requirement and the application of prosecution history estoppel to limit the scope of the doctrine of equivalents, is unlikely to be forestalled (as so much of the Federal Circuit's jurisprudence has been lately) by the Supreme Court, since it is in line with the Court's inclination that patents should be parsimoniously granted.
In this climate, conventional claims to pharmaceutical compositions may be at risk. In the biologics area, patent disclosures typically contain specific information relating to isolating a gene encoding the biologic compound and methods for producing a sufficient amount of the protein to determine its properties. Disclosure relating to producing a pharmaceutical from such a biologic compound tends to be more generic. In addition, biological deposits of functional cell lines for producing the biologic are rarely made, in part to protect against a competitor, especially a foreign competitor, obtaining a sample of the cells once a patent is granted in the U.S.
The capacity for a skilled artisan to use the patent disclosure to produce a biologic drug implicates the "quid pro quo" nature of the patent grant. The inventor obtains the exclusive right only because she fully discloses her invention, with the expectation that the skilled worker will be able to practice the claimed invention throughout its full scope once the patent has expired. Assertions (or worse, circumstances) to the effect that a skilled worker could not practice a pharmaceutical composition claim to a biologic, either because of the inherent complexity of the drug, differences in cell lines used to produce the drug, or failure to disclose necessary methods for producing or formulating the drug, could result in invalidating such claims. And as the number of "position papers" and other publicly-available sources of such claims increase, so does the potential for savvy Examiners to use such statements to make procuring pharmaceutical composition claims for biologic drugs harder to obtain.
Since the assertions are based on real complexities in producing biologic drugs, and these complexities impact safety and efficacy, the solution is not to stop raising the issues. Rather, perhaps it would make more sense to focus on whether follow-on biologic drug producers are of "ordinary skill" in the art. Alternatively, patent claims may more productively be directed toward the biologic agent per se rather than to pharmaceutical compositions. Although it is unlikely that a particular commercial strain or cell line will be available prior to patenting, deposit of an equivalent (or at least sufficient) cell line may be considered (although this will risk a competitor obtaining the cells). As with some conventional pharmaceuticals, it may be possible to patent particularly advantageous synthesis or formulation methods, or to simply increase the extent of patent disclosure relating to actual production of a biologic drug.
No matter how it is done, such disclosure will be important for a number of sound policy reasons. Post patent expiry, disclosure is in the public interest and satisfies the patent quid pro quo. Innovators are protected by data exclusivity, since the patent disclosure is the floor, the minimum that is required, and there is a wealth of information relating to the regulatory process that is not required to be contained in a patent specification. Also, providing increased disclosure can be used as leverage for obtaining political concessions, such as increased market and data exclusivity. And finally, it is just good corporate citizenship, at a time when many voices are inclined to blame drug companies for the reality that producing new drugs, particularly biologic drugs, is a capital-intensive enterprise requiring sufficient return on investment to obtain the necessary capital. Such efforts to convince policymakers of these economic realities, in the face of the political clarion call for lower drug costs at any price, will be more and more important as the cost for new drugs increases.
Methodology for estimating the Loss of Exclusivity (Date when generics can enter market) in US for selected biologic drugs".
Please provide some very, very specific articles or PPTs on above mentioned topic.
Thanks & Regards
Amit Srivastava
Posted by: amit | July 30, 2008 at 09:20 AM