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 .
Response to Amendments
Claims 1, 3, 5-7, 11, 18-24, 26, 27, 30, 33, 35, 37, 39-40, and 43-46 are pending in the amendment submitted 12/30/25.
Election/Restrictions
Applicant’s election of Group I and the species of compound 17 (from claim 18):
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in the reply filed on December 30, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant has indicated the election reads on claims 1, 3, 5-7, 11, 18-24, 26, 27, 30, 33, 35, 37, 39, 40, and 44. The examiner has included compound 18, being the cis- isomer, as it would pose no undue burden in examination to include as the search for one would reveal any pertinent art to the other.
While the election has been treated as “without traverse”, it is noted applicant requests reconsideration of the requirement in light of the claim amendments, asserting there is unity of invention in that all compounds contain a common structure:
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where L-1 and L-2 are 1 or 2 carbons to make a 5-7 member hetero-ring, and is a special technical feature required for unity. While applicant has amended the claims and narrowed the scope rendering the art used in breaking unity inapplicable, the technical feature of the compounds (as shown below in the rejections under 103) does not make a contribution over the art, and thus the claims remain lacking unity and the restriction requirement is maintained.
Claims 43, 45, and 46 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/30/25.
Priority
The instant application is a national stage filing of PCT/CN2021/116418, filed 09/03/2021, and claims the benefit of priority to CN 202010921153.5, filed 09/04/2020. No certified translation of the foreign application has been provided.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7/26/23, 8/28/24, 3/25/25, and 5/21/26 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
References not in English have been considered to the extent of any submitted English translation/abstract, statement of relevance, or identified English equivalent.
It is noted that several ISRs are cited on the IDS submissions and have been considered to the extent of the document submitted, however any document/reference cited on the ISR has not been considered unless provided and identified on an IDS.
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.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 5-7, 11, 18-24, 26, 27, 30, 33, 35, 37, 39, 40, and 44 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.
The written description requirement of 35 U.S.C. 112(a) is satisfied only if the specification reasonably conveys to one of ordinary skill in the art that the inventor had possession of the claimed subject matter as of the filing date (See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010); MPEP § 2163) and for a broad genus, the specification must disclose either a representative number of species or structural features common to the members of the genus sufficient to show possession of the full claimed scope (See Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1568-69 (Fed. Cir. 1997); MPEP § 2163).
In the instant case the claims are directed to the prodrug forms of the compounds, which is a functional descriptor and does not impart any particular structure that would be required. To this point, the specification defines prodrug (spanning pages 36 and 37) with the art-recognized definition as a drug that is converted into the parent drug in vivo, and that a “prodrug may be, but not limited to, any compound of formula I administered as an ester… Another examples of the prodrug may be a short peptide…” (page 37). However, it does not provide sufficient representative species, common structural features, or structure-function correlation to reasonably convey possession of the full scope of the claimed genus.
The artisan understands that prodrug forms are generally determined a posteriori, and it is only through trial and error that prodrugs are identified. The artisan understands the concept of prodrugs, however the artisan does not per se understand what specifically describes a specific prodrug form. The art acknowledges there is no specific definition for prodrug (e.g. page 1, H.-K. HAN. AAPS Pharmsci. (2000) 2(1), article 6, pages 1-11), but that in general, the 'prodrug' is an inactivated form of the drug that activates in vivo to the active form. While some prodrugs are simply esters or salts, other prodrug forms are not chemically or structurally related to their active form, one example being glucose as the prodrug form of hydrogen peroxide (Table 1, page 5), as is hypoxanthine, thus posing a problem as to understanding what is the exact prodrug form of a compound, as hydrogen peroxide has two prodrug forms in the limited set of compounds exemplified in Han.
ETTMAYER (P. Ettmayer et al. J. Med. Chem. (2004) 47(10), pages 2393-2404), prodrugs are often accidental discoveries and TESTA (B. Testa. Biochem. Pharm. (2004) 68, pages 2097-2106) teaches that, “A number of challenges await medicinal chemists and biochemists carrying out prodrug research, such as the additional work involved in synthesis, physicochemical profiling, pharmacokinetic profiling and toxicological assessment. Two of these challenges are introduced here, namely biological variability and toxicity potential. The challenge of biological variety results principally but not only from the huge number and evolutionary diversity of enzymes involved in xenobiotic metabolism. Inter- and intra-species differences in the nature of these enzymes, as well as many other differences such as the nature and level of transporters, may render prodrug optimization difficult to predict and achieve.” (page 2098).
Accordingly, claims 1, 3, 5-7, 11, 18-24, 26, 27, 30, 33, 35, 37, 39, 40, and 44 are rejected under 35 U.S.C. 112(a) for lack of adequate written description.
Claims 1, 3, 5-7, 11, 18-24, 26, 27, 30, 33, 35, 37, 39, 40, and 44 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 3, 5-7, 11, 18-24, 26, 27, 30, 33, 35, 37, 39, 40, and 44 recite, “…or stereoisomers, geometric isomers…” and it is unclear how one could have either, as the compounds are drawn as flat molecules lacking any stereochemistry. The claims embrace all stereoisomers and geometric isomers, and it is unclear what is intended to be captured by the recitation. Further, claim 18 incudes the stereoisomers/geometric isomers for the same compound, such as compound 17 and 18, and it is unclear what stereoisomers/geometric isomers could be embraced by the claims. Further, with regards to the prodrugs, claims 1, 3, 5-7, 11, 19-24, 26, 27, 30, 33, 35, 37, 39, 40, and 44, and subsequent dependent claims, recites entirely generic structures of the compound, and it is unclear what would constitute, or distinguish, a ‘prodrug’ from the compound within the structure of the claim.
Additionally, claims 1, 3, 5-7, 11, 18-24, 26, 27, 30, 33, 35, 37, 39, 40, and 44 recite, “…or stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotope labeled analogs thereof.” Each is written in the plural, appearing to require multiple variants of each option simultaneously (e.g. pharmaceutically acceptable salts), and it is unclear whether applicant is intending the plural or if it was intended to be “or a stereoisomer, geometric isomer… thereof" in the singular.
Claims 1 and 11 recite “suitable sites…” Suitable is a relative term, and the claims do not contain any standard by which one would be able to distinguish “suitable” from “unsuitable” sites. Suitability could be based on anything from steric hinderance to functional activity modulations, neither of which is stated in the claims, and thus it is unclear.
Claim 18 recites, “… the compound has the following structure:”, followed by over 100 discrete chemical structures. The claim internally inconsistent, reciting “the compound” and “the structure”, in singular, while reciting a list of compounds. A compound can only have one structure. It appears that the claim would be clear is it recited “… the compound is selected from the following structures:” Further, it is noted that the Markush does not end with “and” or “or” between the final two species.
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.
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, 3, 5-7, 11, 18-24, 26, 27, 30, 33, 35, 37, 39, 40, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over LI, WO 2020/182018 A1, (IDS 3/25/25, English machine translation attached to instant PTO-892) in view of STN RN 246228-62-6 (IDS 5/21/26), PATANI (George A. Patani and Edmond J. LaVoie. Bioisosterism: A Rational Approach in Drug Design. Chem Rev. 1996;96(8):3147-3176), and MEANWELL (Nicholas A. Meanwell. Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54, 2529-2591).
The instant claims are drawn to compounds generally of the formula
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with the elected species being:
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, and the cis- isomer. The claims alternatively generally embrace deuterated forms of the compounds.
Li teaches the compound
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(e.g. compound 1, claim 17), amongst others, in addition to teaching “a stereoisomer, a tautomer, or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or the stable isotope derivative, metabolite or prodrug of the compound” (claim 17). Li teaches the compounds as pharmaceutical compositions for treating PRMT5-related diseases (e.g. claim 18), and the generic compound structure:
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, where Rb can be OH (e.g. claim 5).
In the synthesis of the compound of Li, Li teaches using the compound 1d
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(page 27).
Li does not teach the hydroxyl group:
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specifically in the compound.
RN 246228-62-6 is the compound
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.
Patani teaches that fluorine, hydroxyl, amino, and methyl groups are replacements as isosteres for hydrogen as “a result of the direct adaptation of Grimm’s Hydride Displacement Law.” (page 3152) and that in the compound exemplified, activity was retained within the group. Additionally, Meanwell teaches that deuterium is a isostere for hydrogen (e.g. page 2529 3.1.1 Deuterium as an Isostere of Hydrogen). Meanwell describes the advantages from D/H exchange in modulating metabolism, toxicity, and slowing epimerization (pages 2529-2531).
It would have been obvious to have made the compound of Li with the ring hydroxyl, as Li teaches it is an available option for the ring as a substitution, and Patani teaches that hydroxyl is considered an isostere of hydrogen, such that one would expect it to function in the same manner as the base compound to treating PRMT5-related diseases. Further, the STN RN compound is structurally related to the compound used in the synthesis of compound 1 of Li, one could reasonably substitute it into the reaction to arrive at the instantly claimed compound. Further, it would have been obvious to have made either the cis- or trans- isomer, as Li teaches stereoisomers as alternative embodiments to the compounds, and one would have expected the compounds to function in a similar manner. In addition, it would have been obvious to have made the deuterated version of the compound to gain the advantages detailed in Meanwell because Li teaches that the compound can be made in the D/H substituted form.
Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 5-7, 11, 19-24, 26, 27, 30, 33, 35, 37, 39, 40, and 44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18-21, 23, and 26-32 of copending Application No. 18/560,632 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. ‘632 teaches the compound
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, pharmaceutical compositions, and the use of the compound which anticipates the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. It is noted that ‘632 has been allowed and the provisional nature of the rejection would switch upon its issuance.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Andrew D Kosar whose telephone number is (571)272-0913. The examiner can normally be reached Monday-Friday, 7am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Michener can be reached at 571-272-1600. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Andrew D Kosar/ Supervisory Patent Examiner, Art Unit 1625
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