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 .
Priority
This application, filed 7 November, 2023, is a national stage application of PCT/CN2022/092182, filed 11 May. 2022, which claims foreign benefit of Applications CN202210086937.X, filed 25 January, 2022, CN202111114252.3, filed 23 September, 2021, and CN202110511570.7, filed 11 May, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7 February, 2024, is acknowledged and has been considered.
Status of the Application
Receipt is acknowledged of Applicant’s claimed invention, filed 7 November, 2023, in the matter of Application N° 18/289,805. Said documents have been entered on the record.
Claims 1-23 are canceled. Claims 24-43 are new. No new matter was introduced.
Thus, Claims 24-43 represent all claims currently under consideration.
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 24-43 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.
Claim 24 recites “a pharmaceutically acceptable form” of the compound of Formula I selected from “pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, oxynitrides, isotopically labeled compounds, metabolites and prodrugs.” Esters, prodrugs, and metabolites represent structurally distinct compounds, rather than mere alternative forms of the same compound.
However, the specification fails to reasonably convey to one of ordinary skill in the art that the inventors were in possession of ester, prodrug, or metabolite embodiments of the claimed compound at the time of filing. Specifically, the specification does not disclose any representative ester, prodrug, or metabolite structure, nor does it provide structural guidance or defining features sufficient to delineate the scope of such embodiments.
Because esterification, prodrug modification, and metabolic transformation each result in compounds that differ structurally from the compound of Formula I, inclusion of these embodiments in a generic list of pharmaceutically acceptable forms, without corresponding structural disclosure, is insufficient to satisfy the written description requirement of 35 U.S.C. 112(a).
Claims 25-43 either depend from Claim 24, or upon its definition of “a pharmaceutically acceptable form”, and fail to cure the deficiency as described above.
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 24-43 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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “oxynitride” in claim 24 is used by the claim to mean “a compound formed by oxidation of a nitrogen atom in the structure of tertiary amine or a nitrogen-containing (aromatic) heterocyclic compound,” (instant Spec, Pg. 23, Lines 15-16), while the accepted meaning is understood to refer to “inorganic or solid-state materials containing oxygen and nitrogen anions”. The term is indefinite because the specification does not clearly redefine the term.
Formula I contains multiple fixed and additional optional nitrogen atoms, and the claims do not specify which nitrogen atom(s) are subject to oxidation, whether multiple “N-oxide” forms are encompassed, or which nitrogen functionalities are capable of forming the recited oxynitride. As a result, one of ordinary skill in the art cannot reasonably ascertain the metes and bounds of the claimed subject matter.
Claims 25-43 either depend from Claim 24, or upon its definition of “a pharmaceutically acceptable form”, and fail to cure the deficiency as described above.
Additionally, Claim 31 recites alternative sub-formulas I-1 and I-2 and further includes an exception clause that applies “and when R4-1 is H.” However, sub-formula I-1 does not include an R4-1 substituent. As a result, it is unclear how the exception clause applies to embodiments of sub-formula I-1. Because the claim does not clearly indicate whether the recited exception applies to both sub-formulas or only to sub-formula I-2, one of ordinary skill in the art cannot reasonably ascertain the scope of the claim.
Similarly, Claim 32’s I-3, Claim 33’s I-5, Claim 34’s I-8, Claim 35’s I-11, Claim 37’s I-14, and Claim 38’s I-17 do not include an R4-1 substituent.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 24-30 and 40-43 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mevellec et al. (WO 2020/193512 A1, cited in IDS), hereinafter Mevellec.
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Mevellec teaches bicyclic HPK1 inhibitor compounds, compositions, and their use for treating diseases such as cancer (‘512, Abstract), to include Compound 1 (‘512, Pg. 87, Line 16), shown top right, which is fully encompassed by instant Formula I (as in instant Claim 24), shown bottom right, wherein A1-A6 are each independently CH, R1 is Methyl (as in instant Claims 25-28), R2a is H, R2b and R4b, together with the atoms to which they are attached, form a 5-membered heterocyclyl, wherein the heterocyclyl each comprises 1 N atom, pyrrolidine (as in instant Claim 29), R4a is H, and R3 is Hetb, wherein Hetb is a tetrahydropyran (as in instant Claim 30).
Regarding Claim 40, Mevellec teaches a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable addition salt, an N-oxide, or a solvate thereof, and a pharmaceutically acceptable carrier or excipient (‘512, Pg. 9, Line 34-35 and pg. 10, Line 1-2.)
Regarding Claim 41-42, Mevellec teaches the inhibition of HPKl by a provided compound may be useful in treating or preventing, in particular treating, the following non-limiting list of cancers: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectum adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain tumors, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma, and ovarian serous cystadenoma (‘512, Pg. 64, Line 12-19.)
Regarding Claim 43, Mevellec teaches additionally that compositions also prevent or treat the disorders referred to therein (‘512, Pg. 68, Lines 27-28.)
As such, Mevellec anticipates Claims 24-30 and 40-43.
It is noted that the cited reference discloses additional compounds within its described genus that also fall within the scope of Formula I. While anticipation is established by the expressly disclosed exemplified compound discussed above, the disclosure of the broader genus further confirms that the claimed subject matter lacks novelty.
Claim Rejections - 35 USC § 103
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 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 31-38 are rejected under 35 U.S.C. 103 as being unpatentable over Mevellec (WO 2020/193512 A1, cited in IDS.)
The teachings of Mevellec (2020) are set forth in the above 35 U.S.C. 102 Rejections and are incorporated herein. Mevellec discloses a genus of compounds that overlaps the claimed compounds, including compounds useful as HPK1 inhibitors for the treatment of cancer.
Both the instant application and Mevellec disclose genera of Formula I, shown below. The reference’s Formula I has been intentionally rotated to demonstrate identity of the core structures.
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Instant Formula I
‘512, Pg. 5, Line 12, Formula I
The dependent claims addressed below introduce exception clauses that exclude certain specific substituent combinations. However, these exclusions do not remove the claimed compounds from the scope of the overlapping genus disclosed in the prior art, as numerous alternative substituent combinations remain encompassed.
Claim 31 discloses sub-formulas I-1 and I-2 and recites an exception clause that applies when R1 is selected from H, halogen, CN, -NR6eR6r, -C(=O)NR6gR6h, C1-4 alkyl or C3-8 cycloalkyl and when R4-1 is H. Mevellec discloses compounds wherein R1 (reference’s R3a) and R4-1 (stemming from selection of reference’s A1) satisfy the conditional portion of the exception clause (‘512, Pg. 5, Lines 17-19 and Pg. 7, Lines 17-18.) However, the reference further discloses compounds in which A2, A3, A5 and A6 (reference’s A4, A6, A2, and A3) are not all CH and/or A2 (reference’s A4) is CH (‘512, Pg. 5, Lines 17-19.) Accordingly, the exclusionary portion of the exception clause is not met, and the disclosed compounds remain within the scope of the claim.
Similarly, Claim 32 discloses sub-formulas I-3 and I-4 and recites an exception clause with the same conditional portion which is satisfied by the reference. However, the reference further discloses compounds in which A3, A5 and A6 (reference’s A6, A2, and A3) are not all CH and/or R2-1 (off reference’s A4) is N (‘512, Pg. 5, Lines 17-19.) Accordingly, the exclusionary portion of the exception clause is not met, and the disclosed compounds remain within the scope of the claim.
Similarly, Claim 33 discloses sub-formulas I-5, I-6, and I-7 and recites an exception clause with the same conditional portion which is satisfied by the reference. However, the reference further discloses compounds in which A5 and A6 (reference’s A2 and A3) are not all CH and/or R2-1 (off reference’s A4) is N (‘512, Pg. 5, Lines 17-19.) Accordingly, the exclusionary portion of the exception clause is not met, and the disclosed compounds remain within the scope of the claim.
Similarly, Claim 34 discloses sub-formulas I-8, I-9, and I-10 and recites an exception clause with the same conditional portion which is satisfied by the reference. However, the reference further discloses compounds in which A6 (reference’s A3) is N and/or R2-1 (off reference’s A4) is N (‘512, Pg. 5, Lines 17-19.) Accordingly, the exclusionary portion of the exception clause is not met, and the disclosed compounds remain within the scope of the claim.
Similarly, Claim 35 discloses sub-formulas I-11, I-12, and I-13 and recites an exception clause with the same conditional portion which is satisfied by the reference. However, the reference further discloses compounds in which R2-1 is absent, and therefore not H, if reference’s A4 is N and/or R6-1 is absent, and therefore not H, if reference’s A3 is N (‘512, Pg. 5, Lines 17-19.) Accordingly, the exclusionary portion of the exception clause is not met, and the disclosed compounds remain within the scope of the claim.
Similarly, Claim 37 discloses sub-formulas I-14, I-15, and I-16 and recites an exception clause with the same conditional portion which is satisfied by the reference. However, the reference further discloses compounds in which R2-1 is absent, and therefore not H, if reference’s A4 is N and/or R6-1 is absent, and therefore not H, if reference’s A3 is N (‘512, Pg. 5, Lines 17-19.) Accordingly, the exclusionary portion of the exception clause is not met, and the disclosed compounds remain within the scope of the claim.
Similarly, Claim 38 discloses sub-formulas I-17, I-18, I-19 and I-20 and recites an exception clause with the same conditional portion which is satisfied by the reference. However, the reference further discloses compounds in which R2-1 is absent, and therefore not H, if reference’s A4 is N and/or R6-1 is absent, and therefore not H, if reference’s A3 is N (‘512, Pg. 5, Lines 17-19.) Accordingly, the exclusionary portion of the exception clause is not met, and the disclosed compounds remain within the scope of the claim.
Claim 36 discloses sub-formulas I-13-1, which is instant Formula I but defines R1 as
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, wherein R1a and R1b are both independently H. Mevellec Formula I discloses R3a (equivalent to instant R1) is selected from cyano substituted with -C(=O)-NR6gR6h, wherein R6g is H and R6h is H (‘512, Pg. 7, Lines 17-19.)
It would have been prima facie obvious to one of ordinary skill in the art to select compounds falling within the overlapping genus while excluding particular substituent combinations as a matter of routine optimization or design choice, especially where the prior art teaches the genus as useful for the same biological target and therapeutic indication. One of ordinary skill in the art would have been motivated to select alternative substituent combinations within the disclosed genus while avoiding specific combinations, as such selection represents routine modification within a finite set of predictable options. The exception clauses do not result in a structurally or functionally distinct class of compounds sufficient to overcome the prima facie case of obviousness.
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Mevellec (WO 2020/193512 A1, cited in IDS) as applied to Claims 24-38 and 40-43 above, and further in view of St. John and Fotsch (“Mitigating Heterocycle Metabolism in Drug Discovery”, J. Med. Chem. 2012, 55, 6002−6020.)
Regarding Claim 39, Mevellec teaches Compound 8 (‘512, Pg. 89, Co.8), which differs from instant Compound A-1 (instant Specification, Pg. 28, Example 1), only by the aza substitution at the position marked below (instant A3 and ‘512’s A6.)
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‘512, Pg. 89, Co.8
Instant Compound A-1, Claim 39
Mevellec fails to teach the A6 position can be N in its Formula I.
However, St. John and Fotsch teach saturated heterocycles are most prone to metabolism at the position adjacent to or directly on the heteroatom. Therefore, strategies used to reduce metabolism of these rings involve techniques to block the site of metabolism, change the electronics of the ring, or reduce the hydrophobicity of the ring (2012, Introduction, Pg. 6011, Table 3 and Pg. 6014 Fig 40.)
The following Examiner’s reference table uses the same exemplified species disclosed by Mevellec for direct comparison, while noting that Mevellec further discloses and exemplifies additional species within its genus that likewise demonstrate routine and modest substituent variations analogous to those recited in the instant claimed species.
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‘512, Pg. 89, Co.8
Instant Claim 39
Pg. 17 Row 1 Col 1
Instant Claim 39
Pg. 17 Row 1 Col 2
Instant Claim 39
Pg. 17 Row 3 Col 1
Instant Claim 39
Pg. 17 Row 3 Col 2
Although the specific methyl and halogen substituents recited in the claimed species are not expressly permitted within Mevellec’s substituent definitions, the modifications shown in the table represent modest, peripheral changes to the same core scaffold and do not alter the fundamental structure or biological target of the compounds. Moreover, the instant specification does not provide data or disclosure demonstrating any unexpected results or criticality associated with those substituent changes.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify Mevellec’s exemplified compounds to arrive at the instant claimed species, as the claimed compounds retain an identical core scaffold and differ only by minor and routine substituent changes, including alkyl, halo, or aza substitution at peripheral ring positions.
One would have been motivated to make such modifications because Mevellec teaches the core scaffold as useful for HPK1 inhibition and cancer treatment, and St. John and Fotsch further teaches that replacement of a ring carbon with a nitrogen atom (aza substitution) is a routine medicinal chemistry strategy for mitigating heterocycle metabolism. Additionally, other well-established, commonly employed modifications, such as alkyl and halo substitutions, are used to optimize pharmacological properties without altering the fundamental activity of the core scaffold.
One would have had a reasonable expectation of success in making these modifications because the substitutions represent predictable variations within a finite set of known options applied to an unchanged core structure targeting the same biological pathway, and the instant specification does not provide evidence of unexpected results or criticality associated with the recited substituent changes.
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 24-38 and 40-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-22 and 24-26 of U.S. Patent No. 10,952,995 and Claims 1-2, 4-5, 7-16, and 18-20 of U.S. Patent No. 11,944,606.
Although the claims at issue are not identical, they are not patentably distinct from each other because the three sets of claims teach compounds sharing the same core scaffold and directed to the same HPK1 pathway and therapeutic use, and the differences between the claimed compounds and those of the reference patents are limited to routine substituent variations that would have been obvious to one of ordinary skill in the art.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Donna M. Nestor whose telephone number is (703)756-5316. The examiner can normally be reached generally (w/flex): 5:30a-5p EST M-Th.
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/D.M.N./ Examiner, Art Unit 1627
/SARAH PIHONAK/ Primary Examiner, Art Unit 1627