Biotech products inherently variable and unpredictable, says BIO (14/7/2003)

The biotech industry claims processes like genetic engineering are no different from conventional breeding and that biotech products are substantially equivalent to conventional products.

At least, they claim that until they want to establish Intellectual Property Rights!

Then they say that their products are unique and non-reproducible, being in a different class in terms of variability and predictability which means it could be dangerous to even try and do so!!

This is from PatentWatchProject.
The Biotech Industry Organization has filed a Citizen's Petition with the FDA seeking to limit the applicability of Hatch-Waxman to  "biologics". Below is attached a Nature:Biotechnology Article detailing what is at stake.

In the past, the straight PhRMA industry could not escape the limits placed upon New Chemical Entities (NCE) under Hatch-Waxman. Such simple molecules could be manufactured easily by generic companies, and it could be expected that a competent generics company could make a bioequivalent NCE.

The BIO petition, points out that the situation is not quite as simple for "biologics", molecules such as recombinant proteins that are used therapeutically and already have FDA approval. The article below states that "Slightly different versions of such products from different manufacturers, for example, may differ in terms of their immunogenicity or in other properties that could affect safety, efficacy  or both." The BIO petition itself makes the following statement:

"Biological products are inherently variable and complex products derived from living sources, and they are susceptible even to slight changes in the manufacturing process."

"In contrast to other drug products, biologically derived products' manufacturing processes involve numerous complicated steps based upon the production and secretion of the biologically active molecule by living cells or organisms, the responses of which are inherently variable."

"Today, unpredictable changes in a product's safety profile (i.e., changes in pharmacokinetics, pharmacodynamic efficacy and safety, including immunogenicity) due to manufacturing changes present major dilemmas for developers of biologically derived products."

All that may be true, and if so, it speaks to the immense *unpredictability* of the biotech venture. Although biotech apologists (e.g., those in crop biotech) spout to the layman of the "precision" of their methods, such is now admittedly not the case. A given DNA expression unit may give rise to variant proteins, depending upon what host cell it is expressed in (bacterial or plant or mammalian) and depending upon how it becomes inserted (i.e., where in the host cell genome) and depending upon the type of glycosylation of the resultant protein and  dependent upon the methylation and/or the folding of the protein and dependent upon what sorts of alternative splicing and RNA editing and other phenomena take place during the making of the protein.

What does all this have to do with IPRs (industrial privilege regimes)?

One purpose of the BIO petition is to maintain marketplace monopoly for member companies that  have therapeutic biologics  coming off-patent or soon to be so. Delaying the entry of biogenerics is, in part, a proxy for unjust timewise patent term extension. What is unspoken (and unspeakable) in the BIO petition is how its charges may impugn the validity of the very patents that BIO might want to extend. How can this be so?

Speaking in general terms (and not to the merits of any particular patent), many biologics are patented in terms of the polynucleotide that encodes them, or the method of expression in a host cell, or the isolated recombinant biologic itself.

It is currently accepted by Federal Courts (per the Lourie Doctrine) that a patent must have an "adequate written description" at the time of filing:  a patentee must describe the invention, the full scope thereof, not merely show enough to render such scope obvious to follow-on inventors, and not merely enough to enable others to practice the invention. This doctrine appears to apply particularly in so-called "unpredictable arts". In view of the BIO anti-biogeneric petition, it can be seen that the manufacture of recombinant biologics may be one such art. The phenomena decribed supra (e.g., alternate splicing) likely create a class of invention which are characterized by factors not reasonably predictable in terms of the ordinary skill in the art. The patentee for biologics could not predict the vast change in immunogenicity which would occur when a later practitioner tries to replicate the patented biologic: therefore, the patent should not be extended to cover that "different" biologic (as BIO might assert it to be)! Arguing that the patent covers this differently-acting biologic would appear to be an admission that a portion of the claims lacks adequate written description.

Some BIO-member company may want to have it both ways: argue that the biogenerics are different from the patented products they sell, but are still covered by their patents (which don't provide an adequate written description of these allegedly "different" biogenerics).

AIDS activists should follow the IPR issues associated with biologics very closely now and in the future. One need look no further than the cost of FUZEON. If one were to inspect the basic patent for the peptide itself, issued in 1995, it makes no mention and little hint of the "costly manufacturing process" which occurs in Colorado to make what is sold as Fuzeon; it merely makes a throwaway mentiion of generic recombinant techniques that can potentially be used ("The peptides of the invention may be synthesized or prepared by techniques well known in the art").

And yet, the owner of that patent is going to scream long and loud when a generic manufacturer wants to enter the market after expiry of that basic patent-of-sparse-disclosure.

Give a little, get a lot: that is what patents often do.

-Peter DiMauro, Director, PatentWatchProject, Washington DC  (who is not a lawyer and none of this is legal advice)

Nature:Biotechnology July 2003 Volume 21 Number 7 pp
721 - 722

Lawsuits anticipated on generic biologicals front
Jeffrey L. Fox
Washington, DC, USA

Late in April, the Biotechnology Industry Organization (BIO; Washington, DC, USA) submitted a citizen's petition to the US Food and Drug Administration (FDA; Rockville, MD, USA), requesting an open public discussion of agency policy regarding "follow-on" biologics-that is, therapeutic proteins and other biotechnology products that may someday be marketed as generic products. Agency officials are granted 180 days before they are required to respond to the BIO petition, and so far are not showing signs of rushing pell-mell into this potential policy quagmire.

BIO brought this petition to the FDA in part as a response to informal public statements made by several top FDA officials indicating a growing willingness to consider at least certain biotech products under an evaluative umbrella similar to the one being applied to conventional small molecular drug entities. Although muted in tone, BIO's petition lays the groundwork for a more combative approach if FDA aggressively adopts a pro-generics approach regarding biotechnology-derived therapeutics or recombinant hormones, such as human insulin and growth hormone, whose patents will be lapsing in the United States relatively soon, and even sooner in Europe (see Box 1). "These issues are percolating at FDA and will undoubtedly result in litigation" against the FDA if BIO's concerns are not taken seriously, says Steve Lawton, BIO's vice president for regulatory affairs and general counsel.

Since Congress enacted the Hatch-Waxman amendments to the Federal Food, Drug and Cosmetic Act (FDC) in 1984,  drug companies are not required to conduct a full battery of human clinical tests to prove that generic small molecule products are as safe and efficacious as the original products approved by the FDA. Instead, under section 505(b)(2) of the FDC, generic drug producers can cite others' data in addition to their own data when their product is slightly different from the original. This option has typically been used for a change in dosage or formulation of a previously approved drug, but BIO worries that biogenerics could also be accepted through this 505(b)(2) process.

The BIO petition asserts that new drug approvals filed under section 505(b)(2) "cannot scientifically be applied to therapeutic protein products." Slightly different versions of such products from different manufacturers, for example, may differ in terms of their immunogenicity or in other properties that could affect safety, efficacy or both (Nat. Biotechnol. 19, 117-120, 2001). In this context, BIO believes that FDA approval of any follow-on biotechnology therapeutics should be based instead on a full complement of original non-clinical and clinical data because of "the unique scientific nature of biotechnology products." Without this information, according to a BIO statement, "the follow-on products could pose an unnecessary and potentially serious risk to patients."

Political pressures further complicate these matters, of course. FDA Commissioner Mark McClellan and other administration officials recognize that generics can save consumers money. "Encouraging rapid and fair access to generic medications ... is, therefore, one of my major priorities," McClellan told a congressional committee in March. "FDA has to do its part to make these products available." Simultaneously, FDA officials also are encouraging pioneering efforts of the biotechnology and nongeneric pharmaceutical industry sectors, making for a delicate balancing act. BIO's Lawton says the forthcoming policy debate with the FDA could go in one of several ways, but litigation now seems more likely than a simple or early resolution. "This saga will play out over the next several years," he predicts.

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