DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election without traverse of Group I (drawn to a compounds/pharmaceutical composition), in the reply filed on 07/07/2025 is acknowledged.
Claims 1, 10-14, 16-17, 21-22, 28-29, 43-44, and 46-49 are pending of which claims 30 and 41 in Group II and III, are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. The restriction requirement is still deemed proper and is made Final.
Pending claims 1, 10-14, 16-17, 21-22, 28-29, 43-44, and 46-49 have been examined on the merits.
Please note, for clarity of the record, Applicant ’s election of the following compound
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During the course of examination, prior art was identified that relates to non-elected
subject matter. In the interest of compact prosecution, that prior art has been applied to the
generic claims, as discussed below.
Notice of Claim Withdrawal
Newly added claims 45-46 and 50-51, drawn to nonelected Group II and III, are withdrawn from further consideration. Additionally, because the combined teachings of the prior art, as indicated in the 103 rejection, teach the elected compound, thus claims 13, 14 and 16-17 are withdrawn from further consideration.
Withdrawn Rejections
The rejection of Claims 1, 3, 8-9, 12, 21-22 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Llanos et al. Eur J Med Chem. 2017 Nov 10;140:52-64 in view of Patani et al. Chem Rev. 1996 Dec 19;96(8):3147-3176, Gunatilaka et al. (US2011/0230551), Ritchie et al. Eur J Med Chem. 2016 Nov 29;124:1057-1068 is withdrawn in view of the claim amendment and the withdrawn claim.
Maintained Claim Objections
Claims 1, 16, 28, 43, 47 and 48 recite list of substituents with the phrase “and” instead of “or” to indicate alternative options. However, using the phrase “and” in such a list implies that all substituents must be present together, which may not reflect the intended purpose. Therefore, for clarity and proper interpretation, Applicant is required to correct the claims by replacing “and” with the phrase “or”.
New Grounds of Rejection due to Claim Amendment and Newly added Claims
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 10-14, 16-17, 21-22, 28-29, 43-44, and 47-49 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane), the Federal Circuit noted the importance of an application's disclosure and stated, "the hallmark of written description is disclosure." A disclosure adequately describes an invention when it "reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Id. at 1351. "A 'mere wish or plan' for obtaining the claimed invention is not adequate written description." Centocor Ortho Biotech, Inc. v. Abbott Labs, 636 F.3d 1341, 1348 (Fed. Cir. 2011).
What is required to meet the written description requirement "varies with the nature and
scope of the invention at issue, and with the scientific and technologic knowledge already in
existence." Capon v. Eshhar, 418 F.3d 1349, 1357 (Fed. Cir. 2005). The Federal Circuit
explained what is required to meet the written description requirement in Ariad Pharm., Inc. v.
Eli Lilly & Co.:
This inquiry, as we have long held, is a question of fact. Ralston Purina, 772 F.2d at 575. Thus, we have recognized that determining whether a patent complies with the written description requirement will necessarily vary depending on the context. Capon v. Eshhar, 418 F .3d 1349, 1357-58 (Fed. Cir. 2005). Specifically, the level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. Id. For generic claims, we have set forth a number of factors for evaluating the adequacy of the disclosure, including "the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue." Id. at 1359.
A written description of a chemical genus "requires a precise definition, such as by
structure, formula, [or] chemical name" of the claimed subject matter sufficient to distinguish it
from other materials. Regents of the Univ. of Cal. v. Eli Lilly & Co., 199 F.3d 1559, 1568 (Fed.
Cir. 1997). The Federal Circuit reflected on Eli Lil/yin Ariadwhile explaining how to sufficiently
describe of a genus of compounds:
We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus. Id. at 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. at 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F .3d at 964 (quoting 66 Fed. Reg. 1099 (Jan. 5, 2001). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented age nus and not just a species.
A "representative number of species" must typify the entire claimed genus and account
for variation between the species of the genus.
[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated. Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004).
Claim 1, 43, and 47 recite a compound of compound of Formula I, II and III wherein substituents are selected from an extensive set of chemical groups. The size of this genus of claimed compounds may be roughly determined by cumulatively multiplying the number of possibilities, n, for each possible substitution around the rings, specifically at the R1, R2, R3, R4, R5, Rz, Rx and Ry:
(#permutations at R1) x (#permutations at R2) x (#permutations at R3) x (#permutations at R4) x (#permutations at R5) x (#permutations at Rz) x (#permutations at Rx) x (#permutations at Ry) = Total compounds
Taking the R1 or R2 as an example, the number of possible substitutions is not limited, thus, a conservative estimate of the number of possible substitutions would be in the thousands
(103) at a minimum. By inserting the optionally substituted groups into the equation, these estimates yield results in the billions (1012) of compounds making up the claimed genus.
By contrast to billions of claimed compounds, the specification provides very few species
of compounds typifying the claimed genus. For example, the specification (page 27-28; page 44-45) depicts about 12 species with very little variation at R1 and R2, e.g., when they are N(R3)(R4), the specification only discloses species R3 and R4 to a methyl only. Therefore, the 12 species of as presented in the specification and claims 1, 43 and 47 offered to support the genus of billions of compounds account for very little variation as compared to the claimed genus. These 12 supporting species, which lacks variation among the substituents, cannot possibly account for the variability found across a genus that encompasses billions of compounds.
Chemistry is generally considered to be unpredictable and/or have unpredictable factors.
See, e.g. ln re Carleton, 599 F.2d 1021, 202 USPQ 165,170 (CCPA 1979) ("Although there is a
vast amount of knowledge about general relationships in the chemical arts, chemistry is still
largely empirical, and there is often great difficulty in predicting precisely how a given compound will behave."). The pharmaceutical arts, that is the use of a chemical compound to affect a desired physiological activity, is generally considered to be unpredictable and/or have
unpredictable factors. See, e.g., In re Fisher, 427 F.2d 833, 839 (CCPA 1970) ("In cases
involving unpredictable factors, such as most chemical reactions and physiological activity, the
scope of enablement obviously varies inversely with the degree of unpredictability of the factors
involved (emphasis added); In re Bowden, 183 F.2d 115, 86 USPQ 419, 423 ("chemical reactions frequently are unpredictable").
Considering the unpredictability found in organic synthesis, exchanging even one
substituent for another cannot be considered a foregone conclusion. Accordingly, when a claim
presents a genus with substantial variation as that currently presented by claims 1, 43 and 47, the disclosure must adequately reflect such variation with a representative number of species.
The lack of any disclosure of examples may be considered in determining whether a claimed invention was adequately described. Boston Scientific Corp. v. Johnson & Johnson, 647 F.3d
1353 (Fed. Cir. 2011).
As is the case here, very few examples do not provide a "representative number of
species" for an unpredictable art such as a chemistry. See, e.g., Ariad, 598 F.3d at 1354-55
(claiming that the inventor has an obligation to disclose examples when the art is unpredictable).
Synthesized Species
Claims 1, 43 and 47 are directed to a broad genus of compounds defined by Formula I, II or III, encompassing numerous possible substituents and structural variations. However, the specification discloses only a single synthetic example, compound ASR490, which is derived from Withaferin A. The specification fails to provide representative examples for the remaining members of the claimed genus. The disclosure of one species is insufficient to demonstrate full possession of structurally diverse genus, thus the specification does not reasonably convey to a person of ordinary skill in the art (POSITA) that Applicant has possession of the full scope of the claimed genus at the time of filing.
The specification’s failures to disclose details regarding the synthesis of compounds, further supports the conclusion that the specification lacks adequate written description of the claimed subject matter.
New Grounds of Rejection due to claim amendment and newly added claim
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office
action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 10-14, 16-17, 21-22, 28-29, 43-44, and 47-49 are rejected under 35 U.S.C. 103 as being unpatentable over Motiwala et al. ACS Med Chem Lett. 2013 Nov 14;4(11):1069–73, Ali et al., J.Chem.Soc.Pak., Vol. 36, No. 1, 2014. P.150-169, Llanos et al. Eur J Med Chem. 2017 Nov 10;140:52-64, Patani et al. Chem Rev. 1996 Dec 19;96(8):3147-3176, Ritchie et al. Eur J Med Chem. 2016 Nov 29;124:1057-1068.
Regarding claims 1, 28-29, 44, and 49, Motiwala (page 1069) teaches preparation of a library of withalongolide A analogs, including modifications bearing a hydroxyl instead of a methyl group at position 19 as disclosed in the parent compound. For example, Motiwala (page 1070, scheme 2) teaches compound 14, wherein R2 is N(CH3)(CH3), bearing a hydroxyl group at position 19.
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Given that position 19 can either be a methyl or hydroxyl group, this disclosure demonstrates that hydroxyl and methyl group can be used interchangeably as a routine strategy to expand library diversity. This is further supported by Ali (page 155, Fig. 3), who discloses hydroxyl and methyl groups are categorized as classical bioisosteres, indicating that they are recognized as equivalent substituents. In contrast to Motiwala and Llanos (page 54), who teaches a withaferin
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A- based library, wherein the analogous compounds bearing a methyl group at position 19.
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Therefore, a POSITA would recognize that the combined teachings of Motiwala and Llanos in view of Ali disclose that hydroxyl and methyl substituents at position 19 are interchangeable, making such substitution a predictable optimization to enhance the diversity and potency of the compound library, to arrive at the claimed invention.
Regarding excipient and pharmaceutically acceptable carrier, although, the combined teachings of Motiwala and Llanos do not explicitly describe excipients or pharmaceutical acceptable carriers, however, they disclose that withanolide analogs are intended for therapeutic use and are evaluated for cytotoxic activity, IC50 data, in biological systems. Therefore, a POSITA would understand that compounds evaluated for biological activity must be dissolved or dispersed in a suitable vehicle to testing. In fact, both Motiwala and Llanos report IC50 values for multiple withanolide analogs, which indicate that the compound was indeed formulated in a carrier such as DMSO, as disclosed by Lamos, compatible with the assay. Therefore, although the prior art does not explicitly use the phrase “excipient” or “pharmaceutically acceptable carrier,” the reported experimental data inherently reflect the use of such formulation components.
Regarding claims 10-12, 21-22, 43, and 47-48, Motiwala does not explicitly teach R2 is a thiophene, furan, or pyridine.
However, Llanos (page 54, Scheme 1), and as applied to claim 1 above, teaches a compound 16, wherein R1 and R2 and 3-furanyl,
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and m is 0. While, Llanos only teaches 3-furan but not 2-furan substituent, Yousuf (abstract, scheme 2), however, discloses a library of
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withaferin A-derivatives in which 2-furan is used as a substituent. This demonstrates that 2-
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furanyl groups were already known and used in the art in similar scaffolds, as part of routine optimization of withaferin A analog library. Thus, since both Llamos and Yousuf’s teachings encompass the same structural class of withanolide analogs, thus, a POSITA would recognize that 2-furan and 3-furan are closely related positional isomers and are used to expand heteroaromatic diversity to arrive at the claimed invention. Although Llamos and Yosuf do not disclose thiophene substitution, however, Ali (page 155) discloses that oxygen and sulfur are
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classical biososteres, indicating they are interchangeable. This is supported by Patani (page 3155), indicating that “Replacement of the sulfur atom at C-8 with the oxygen or selenium atom, another well-known divalent isosteric replacement, resulted in weaker activity relative to the thio analogue.” It is important to note, a weaker binding does not necessarily point to inferiority, because weaker binding strength could reduce off-target binding and thereby improve the side-effect profile, while preserving the desired biological activity. Therefore, a POSITA would recognize oxygen and sulfur substituent are classical bioisosteres and are therefore expect to display comparable biological effects. This is furthermore supported by Ali (page 158), identifying furan, thiophen belong to the same ring equivalent heteroaromatic scaffolds, which
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also include pyridine. Therefore, a POSITA would have also recognized thiophen and pyridine as a predictable alternative to furan. This is also supported by Patani (page 3158), disclosing that thiophen and pyridine as classical bioisostere or ring equivalent. Therefore, because these heteroaromatic rings are well-recognized class of biososterric alternatives, a POSITA would have been motivated to substitute furan with either thiophen or pyridine with a reasonable expectation of similar biological activity to expand the compound library. Hence, a POSITA would have been motivated to combine the teachings of Motiwala, Patani, Yosuf, Ali, and Llanos to expand the analog library in the search for improved lead compounds and arrive at the claimed invention.
Regarding 2-pyridine, Ritchie (1059-1063) teaches that the presence of nitrogen adjacent to the substitution (i.e., at the 2-position or 2-pyrdidine) provides a beneficial effect by
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reducing CYP3A4 inhibition. Ritchie (1061-1063) also teaches that the 2-pyridine has greater impact on CYP450 3A4 or better ADME profile compared to 3- and 4-pyridine. Therefore, it would have been obvious that a POSITA would consider replacing benzene ring from Motiwala’s teachings with 2-pyridine, in view of Ritchie’s disclosure, to arrive at the claimed invention, because 2-pyridine is a preferred substituent over 3- or 4-pyridine based on its improved ADME profile; particularly lower CYP3A4 inhibition which can potentially improve pharmacokinetic properties of the drug. Moreover, the combined prior art teaches that furan, thiophene and pyridine are ring-equivalent heteroaromatics. In the elected species, R2 is a pyridine, whereas the combined prior art discloses furan at that position. Given they are bioisosteric equivalence, a POSITA would reasonably substitute a furan for a pyridine to arrive at the elected species.
Response to argument
Applicant argues that the previously cited combined prior art does not teach or suggest the claimed compound and notes that the claims were indicated as allowable. However, Applicant argument is not persuasive because the prior Office Action was based on claim scope directed to a different formula that has since been cancelled. For example, claim 1 has been amended and now focused on a selected formula, e.g., Formula II, from among previously recited alternatives (Formula I-III), and the current rejection is based on that specific selection and as well as the newly added claims. Because Formula II is now the subject matter of claim 1 which was not previously examined, the earlier Office Action does not reflect the current scope of claim 1, thus the amended claims were newly examined, and a corresponding search was performed to reflect the amendment. As in indicated above, in the 103 rejection, the newly combined prior art teaches the claim subject matter of the selected Formula II, as an example.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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