Lead Compound Approach: An Eternal Standard For Chemical And Pharmaceutical Obviousness At US PTAB?

While the generics wage an uphill battle to

bust patents for new chemical compounds,

with the PTAB’s reliance on the US CAFC’s

eternal and time-tested standard of LCA

framework, it may not be easy to invalidate

compound patents even under the

preponderance of evidence standard...

It is all about reinforcing the lead compound

approach (LCA) for structural obviousness

determination of new chemical compounds in

chemical and pharmaceutical patents, which

is trending at the United States Patent Trial

and Appeal Board (US PTAB)! Synchronizing with

the United States Court of Appeals for Federal Circuit

(US CAFC)’s eternal and time-tested standard of LCA

framework, the PTAB issued an Inter Partes Review decision

(IPR 2015-0340 dated August 18, 2017) in Mylan Pharm. v.

AstraZeneca AB¹, to uphold the validity of patent RE44,186

(a reissue of U.S. patent no. 6,395,767) covering claims

directed to AstraZeneca’s Saxagliptin (drug originally

developed by BMS, the active ingredient in Onglyza and

Kombiglyze XR).

The LCA framework and the

characteristics of a lead compound?

In doing so, the PTAB relied on one of the CAFC’s landmark

pronouncements, Ostuka vs Sandoz, wherein evaluation of obviousness in new chemical compounds under the LCA

framework involves a two-pronged inquiry considering

first, whether one of ordinary skill would have selected

one or more lead compounds for further development,

and second, whether the prior art would have supplied

sufficient motivation to modify a lead compound to

arrive at the compound claimed with a reasonable

expectation of success.

A natural outcome of LCA² in obviousness determination

of new chemical compounds is that establishing a reason

for selection of a compound in the prior art as a “lead

compound”³ depends on the functional properties and

limitations of prior art compounds. Thus, under LCA,

the CAFC has laid out the requirement that a compound

which has either a potent and promising activity⁴ in

the prior art may be preferred as a “lead compound” (over

other compounds in the prior art) or a compound which

has some limitations like adverse effects to signify that

this compound may not be the suitable choice (compared to

other compounds in the prior art).

PTAB’s Saxagliptin decision: A snapshot

The challenged patent was RE44,186, a reissue of U.S.

Patent No. 6,395,767 and the challenged claims (claims

1, 2, 4, 6–22, 25–30, 32–37, and 39–42) were directed

to a specific class of “cyclopropyl-fused pyrrolidinebased

inhibitors of dipeptidyl peptidase IV (DP-4)” as

well as methods for treating diabetes, with Saxagliptin

recited in claim 25. Initially, the Board refused to initiate

the petition, but upon Mylan’s petition for rehearing,

the Board reversed and instituted the IPR on grounds of

obviousness.

A. Reasoned selection of a lead compound under the

LCA?

The decision focused primarily on whether the “lead

compound”, compound 25, the compound in Ashworth

(I) reference, asserted by the petitioner would lead to a

conclusion of structural obviousness. The Board highlighted

the structural differences between Saxagliptin and

Ashworth (I) compound with Saxagliptin having 3-hydroxyl

adamantyl in place of cyclohexyl group and also having

a cyclopropyl fusion in the pyrrolidine ring (respective

structures are depicted below for reference)

In addressing lead compound selection, the PTAB

under the preponderance of evidence standard, rejecting

the petitioners’ choice of compound 25 as the lead

compound, reasoned that (i) there was no substantial data

provided to guide the skilled artisan to select compound

25 among the other 2-cyanopyrrolidides for further

modification to develop a DP 4 inhibitor; (ii) stability data of

compound 25 was based on in vitro tests at room

temperature with no reliable information on in vivo stability;

and (iii) evidence showing compound 25 would

have presented additional concern of toxic cyanide release

in vivo to the skilled artisan seeking to develop a DP 4

inhibitor.

Further, the PTAB crediting Patent owner’s testimony,

Dr. Weber based on her contemporaneous experience

when she herself performed a similar lead compound

analysis while working at Merck to develop a DP 4

inhibitor at the time of the invention held that NVPDPP728

and P32/98 were recognized by one of the

skill in the art as the most promising, natural starting

points for further development efforts (as they avoided

stability issues and advanced to clinical trials despite

both being less potent than compound 25) and found

that the petitioners’ testimony, Dr. Rotella’s lead

compound selection of compound 25 was more likely to

be prejudiced by hindsight bias.

B. No reason or motivation to modify the

petitioners’ asserted “lead compound” and secondary

considerations

The PTAB indicated that even if compound 25 was accepted

as the lead compound, the petitioners had not established

by a preponderance of evidence that the skilled artisan

had sufficient reason to modify compound 25 to arrive

at Saxagliptin. The three chemical modifications asserted

by the petitioners were rejected by the PTAB on the basis

that:

(i) a skilled artisan would have no reason to modify

compound 25’s proline pyrrolidine ring by adding a

cyclopropyl group to create Cis 4,5-methanoproline, to

increase the compound’s stability with a reasonable

expectation of success, because there was insufficient

evidence in Hanessian’s reference concerning the

cyclopropanation of proline and the petitioner’s own

expert testimony from Dr. Rotella who admitted

that there was nothing in the literature prior to

invention of Saxagliptin that actually suggested

that cyclopropanation of compound 25 would

improve its stability; with similar considerations to

conclude that there was no reasonable expectation of

increased potency and these modifications were indeed

surprising as supported by the patent owner’s expert

testimony;

(ii) replacing the cyclohexyl group for an adamantyl group

was also not supported by the cited prior art as it related

to N-linked and not C-linked substituents because of

the differences in shape of the resulting molecules and

further the secondary amine disclosed in prior art would

be expected to be less available for cyclization and be

more stable;

(iii) no reasonable expectation that the petitioner’s

proposed modification of hydroxylating the adamantyl

moiety would improve stability or bioavailability of

the molecule, based in part on petitioner’s arguments

being made with regard to adamantane rather than the

adamantyl group in Saxagliptin;

(iv) and the petitioners’ failure to show that a skilled artisan

would have reasonably expected that the combined

modifications would have been successful based on

predictability of the individual modifications.

Further, the PTAB gave credence to the secondary

considerations of non-obviousness, with the patent

owner’s assertions on unexpected results, failure of other

DP 4 inhibitor compounds to obtain FDA approval and

long-felt need despite other DP 4 inhibitor compounds

known in the art being persuasive to its finding of nonobviousness.

Conclusion

The PTAB applying LCA has in the past denied to institute

IPR proceedings for the patent covering drug Emend® (Merck

vs Apotex), because the petitioner-asserted lead compound

“compound 96” failed to qualify due to absence of activity

data. So is the case with Torrent vs Merck concerning

the drug DALIRESP® (as the petitioner failed to explain

how a skilled artisan would have identified two prior art

compounds (DI and DJ) from the list of 147 exemplary

compounds as lead compounds); Mylan vs Gilead (even

assuming that an ordinary artisan would have selected

the lead compound PMPA/tenofavir, the invention cannot

be proved obvious owing to unpredictability of prodrug

strategies); in Ex Parte Yann Foricher and Ex parte Caliguiri

(wherein the PTAB reviewed and reversed the Examiners

finding of obviousness on the basis that the prior art

failed to provide a reason for selection of the asserted lead

compound).

While the generics wage an uphill battle to bust the patents

for new chemical compounds, with the PTAB’s reliance on

LCA, it may not be easy to invalidate the compound patents

even under the preponderance of evidence standard. LCA

framework is here to stay and it may therefore be fair to

conclude that LCA would continue to drive the structural

obviousness analysis of new chemical compounds at CAFC

and the PTAB!

Disclaimer – The views expressed in this article are intended to provide information on intellectual property developments and should not be construed as a legal opinion or advice.