Shamnad had some time back discussed with me the idea of application of the Orphan Drug Act (ODA) to section 3(d) the Indian patent act. Specifically Shamnad had suggested using the ODA test (clinical superiority test based on patient care rather than one on structural similarity) and applying it to section 3(d).
What follows is a brief primer on the ODA and applicability to the Indian act as suggested by Shamnad.
Hence under our patent act, section 3(d) may also be interpreted based on similar guidelines and if appropriate, similar guidelines may be used by our courts to interpret patent claims for new compounds.
Long post follows:
What follows is a brief primer on the ODA and applicability to the Indian act as suggested by Shamnad.
Hence under our patent act, section 3(d) may also be interpreted based on similar guidelines and if appropriate, similar guidelines may be used by our courts to interpret patent claims for new compounds.
Long post follows:
In an earlier post, I had discussed providing for a numerical quantifier for section 3(d) of our patents act and in another discussed of the possibility using an exclusionary definition of the term efficacy as relates to the act. In the exclusionary definition post, I had written about FDA definitions about bio-equivalence and application of those definitions by the CAFC. This post provides a summary of definitions used in US Orphan Drug Act (ODA) to determine whether a drug is same or similar to another. This discussion is helpful to the Indian context because of two reasons: (1) the definitions as provided by the ODA consider similar issues as faced by our Controllers/Courts regarding defining efficacy for same or similar drugs, and (2) they have been applied and tested to specific cases and hence their impact and relative certainty can be measured.
The ODA was enacted by US Congress to help a relatively small number of consumers who suffer from a rare disease as there was not enough incentive for research and development (“R&D”) for those small number of consumers suffering from rare diseases. The ODA provided an incentive to pharmaceutical company manufacturing drug to help those few individuals affected by any one (rare) disease or condition to overcome the financial losses. The incentive was a seven year market exclusivity for discovery of new orphan drugs. Specifically, a drug is an “orphan drug” if it is for a “rare disease or condition” that effects fewer than 200,000 patients in the United States or for which there is no reasonable expectation that the cost of developing the drug for a disease will be recovered from sales in the United States. FDA definition.
A little bit of science and history: Prior to the development of recombinant proteins by the biotechnology industry, simple (and smaller) chemical structures provided a basis for most drugs and two drugs were considered the same if they had the same active moiety. See definitions. “Active moiety means the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.” This approach of designating two structures worked well with small molecules because the chemical structure was a good indicator of a drug’s chemical syntheses. Therefore, changes to the chemical structure (of the active moiety) would most likely result in large pharmacological differences for small molecules produced by chemical syntheses.
This definition, however, does not work for large molecules such as recombinant proteins, polysaccharides or nucleic acids, or genes, or glycoproteins. Living organisms contain genes, a unit of heredity. Genes consist of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). DNA consists of two long polymers of “nucleotides.” Nucleotides are arranged in a DNA molecule and a specific arrangement of the nucleotides is a “DNA sequence.” DNA encodes the information that living cells use to build proteins and other RNA molecules. Proteins are essential parts of organisms and participate in virtually every process within cells. Functions include food digestion, metabolism, muscle formation, cell signaling, immune responses, etc. Proteins are made from amino acids using information encoded in genes. Each protein has its own unique amino acid sequence that is specified by the nucleotide sequence of the gene encoding this protein. The genetic code is a set of three-nucleotide sets called codons and each three-nucleotide combination designates an amino acid. Because DNA contains four nucleotides, the total number of possible codons is 64. Genes encoded in DNA are first transcribed into pre-messenger RNA (mRNA) by proteins such as RNA polymerase. Most organisms then process the pre-mRNA (also known as a primary transcript) using various forms of posttranscriptional modification to form the mature mRNA, which is then used as a template for protein synthesis by the ribosome. (Definitions of gene, protein, nucleic acids, DNA taken and combined from Wikipedia).
Without a proper definition of “sameness,” any market exclusivity for a gene, a protein, nucleotide, or a glycoprotein could be completely valueless, because competitors can easily substitute nucleotides to create a “different” gene coding for an identical protein. In proteins, there is a specific problem, because certain individual amino acids are generally structurally interchangeable (because of their similar basic structure and net charge) without producing a noticeable functional effect.
To address the problems associated with these macromolecules, the ODA restricted the use of active moiety to small drug molecules and provided that large drug molecules cannot contain the “same principal molecular structure.”
Specifically, the definitions provide:
(13) Same drug means:
(i) If it is a drug composed of small molecules, a drug that contains the same active moiety as a previously approved drug and is intended for the same use as the previously approved drug, even if the particular ester or salt (including a salt with hydrogen or coordination bonds) or other noncovalent derivative such as a complex, chelate or clathrate has not been previously approved, except that if the subsequent drug can be shown to be clinically superior to the first drug, it will not be considered to be the same drug.
(ii) If it is a drug composed of large molecules (macromolecules), a drug that contains the same principal molecular structural features (but not necessarily all of the same structural features) and is intended for the same use as a previously approved drug, except that, if the subsequent drug can be shown to be clinically superior, it will not be considered to be the same drug. This criterion will be applied as follows to different kinds of macromolecules:
(A) Two protein drugs would be considered the same if the only differences in structure between them were due to post-translational events or infidelity of translation or transcription or were minor differences in amino acid sequence; other potentially important differences, such as different glycosylation patterns or different tertiary structures, would not cause the drugs to be considered different unless the differences were shown to be clinically superior.
(B) Two polysaccharide drugs would be considered the same if they had identical saccharide repeating units, even if the number of units were to vary and even if there were postpolymerization modifications, unless the subsequent drug could be shown to be clinically superior.
(C) Two polynucleotide drugs consisting of two or more distinct nucleotides would be considered the same if they had an identical sequence of purine and pyrimidine bases (or their derivatives) bound to an identical sugar backbone (ribose, deoxyribose, or modifications of these sugars), unless the subsequent drug were shown to be clinically superior.
(D) Closely related, complex partly definable drugs with similar therapeutic intent, such as two live viral vaccines for the same indication, would be considered the same unless the subsequent drug was shown to be clinically superior.
FDA regulations define a “clinically superior” drug as:
(3) Clinically superior means that a drug is shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug) in one or more of the following ways:
(i) Greater effectiveness than an approved orphan drug (as assessed by effect on a clinically meaningful endpoint in adequate and well controlled clinical trials). Generally, this would represent the same kind of evidence needed to support a comparative effectiveness claim for two different drugs; in most cases, direct comparative clinical trials would be necessary; or
(ii) Greater safety in a substantial portion of the target populations, for example, by the elimination of an ingredient or contaminant that is associated with relatively frequent adverse effects. In some cases, direct comparative clinical trials will be necessary; or
(iii) In unusual cases, where neither greater safety nor greater effectiveness has been shown, a demonstration that the drug otherwise makes a major contribution to patient care.
It can be seen that the clinical superiority test is based on patient care rather than basing the test on structural similarity.
Hence under our patent act, section 3(d) may also be interpreted based on similar guidelines and if appropriate, similar guidelines may be used by our courts to interpret patent claims for new compounds.
Our readers may wonder why I keep providing multiple definitions for section 3(d): The reason is simple-currently there are no guidelines that Assistant Controllers follow while rejecting or allowing patent claims under section 3(d). Each Asstt. Controller applies section 3(d) differently and just about anything is fair game when rejecting applications. The result is a mess. With no clear guideline, both the patentee and public suffer. Rejection of claims under section 3(d) differently leads to insufficient incentive to applicants.
Image from: http://en.wikipedia.org/wiki/Spot_the_difference
Dear Rajiv:
Personally, I think that using the ODA guidelines (i.e. to borrow the concept of clinical superiority from ODA for the purposes of 3d analysis is great.
However, lets look at the ground reality. In the US, drug approval for nornam drugs (not orphan drugs) is not linked to this concept. I would urge you to investigate the clinical basis for approval of enantiomer drug (Esomeprazole) over the possible (if any?) superiority of racemic drug – Omperazole.
Working in the industry, let me tell you this – if the above concept is used for the 3d approval/ rejection, then too, most of the applications for polymorphs/ new salts/ particle size ‘inventions’ would fall down.
Just take a look at most of the applications for polymorphs for instance, and you will not see such data either in orginal spec or in the later file history.
Regards,
Freq. Anon.
Aren’t the ODA definitions part of FDA guidelines? Great idea by the way!
Dear FA,
You’re right: this applies only to the ODA. And not to a regular drug such as nexium, since under current norms, the FDA cannot reject approval for a drug only because it is similar in function to an earlier approved one.
The reason for the ODA related exception stems from the desire to incentivise more orphan drugs by granting a lot more protection (7 years of exclusivity.
No competitor can enter the market during the 7 year exclusivity granted to orphan drugs, even if they do the trials themselves. Further, they cannot even introduce a variant that is similar (not therapeutically different) to the drug molecule under protection..
you’re right: most polymorphs would be rejected if this test were used.
Dear FA: Thank you for the compliments. But the credit for goes to Shamnad as well as he was the one who came up with the idea of applying ODA to section 3(d).
Your comment about enantiomer drugs versus racemic drug is something the FDA has dealt with and is similar to the Human Growth Hormone (hGH) which in itself is a blockbuster drug and does not need any protection from ODA (Genentech/Eli Lilly).
You are also right about most applications failing the test (if adopted).
Dear Shamnad/ Rajiv:
On an unrelated note (not pertaining to new forms of known substances) – but still touching upon clinical superiority:
http://www.medpagetoday.com/MeetingCoverage/ICAD/27576
Was reading this today and thought of posting it here as well.
Regards,
Freq. Anon.
Dear FA,
Can the derivatives/polymorphs (which are generally rejected under 3d, be granted a patent of addition to the parent patent (of parent molecule)? Are there any examples of such in industry? Plz let me know.
regards,
S
Dear S:
I have not really come across many patents of addition, generally.
At least in my reading, I have not seen any pharma company asking for a patent of addition for their 3(d) hit invention by linking it to their basic patent.
Regards,
Freq. Anon.
S @ 5:37 PM: It is extremely unlikely that such a patent (of addition) would ever be granted. Reason is that 3(d) can be applied from both obviousness and subject matter. New patent would be obvious and as a policy matter, ineligible under section 3(d).
I have not come across any such case.
Thanks FA:
interesting piece demonstrating once again that the pharma industry has a bigger problem on its hands than the generic threat i.e. a number of drugs are no better than placebos! very difficult to establish credible efficacy for many of them, but one can be certain that almost all of them will come with side effects.
see this interesting piece:
http://www.wired.com/medtech/drugs/magazine/17-09/ff_placebo_effect?currentPage=all
Thanks FA and Rajiv.
@Rajiv: I really wonder how addition would not be granted? The 3d vaults mainly on “an enhancement of known efficacy”. In patent of addition, it is an improvement or modification of the main invention and does not involve a substantive inventive step. I believe there should be some other practical shortcoming.
thanks,
S
Patent of addition is granted for an improvement. In this case, derivatives themselves are barred under 3d-so a derivative to a derivative would also be barred (as of current reading of the law).
What is being proposed is that each such application be examined from the view point of patient care or efficacy.