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 .
Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on April 10th, 2026 has been entered.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: Claim 13 speaks to the treatment of “ROS1, NTRK, and ALK and drug-resistant kinases thereof”, however, the specification seems to only mention “drug resistant-mutations” (e.g. page 9, line 21-22) (see 112(b)).
Status of the Claims
Claims 1-15 are pending in this application.
Examiner Notes
Claims 3-4, 6, and 9 are free of the prior art, but stand rejected over formal matters herein.
Claim Objections
Claims 1, 5, and 7 are objected to because of the following informalities:
Claim 1 reads: “…wherein the substituted means…” (fifth line from bottom of page 2). Claim should read: “…wherein “the substituted” means…”
Claim 5 reads: “…wherein, the “substituted” means…” (fifth line from bottom of page 4). Claim should read: “…wherein “the substituted” means…” (note that comma after wherein was removed). Claim 7 has the same issue pointed out for claim 5.
Appropriate correction is required.
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 1-15 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 purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.” University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 920 (Fed. Cir. 2004), (quoting Reiffin v. Microsoft Corp., 214 F.3d 1342, 1345 (Fed. Cir. 2000)). To determine whether there is adequate written description support for the genus of methods and means of achieving the claimed properties, the Specification is reviewed for species that achieve the claimed results. "[T]he specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Ariad, 94 USPQ2d at 1170-1171.
Instant claim 1 is drawn to the compounds of Formula I, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates thereof. The specification, however, provides no support for crystalline forms, hydrates, or solvates. The specification merely recites the terms “crystalline form”, “hydrate”, and “solvate” generally, without demonstrating any specific embodiments in which their compounds are prepared as a “crystalline form”, “hydrate”, or “solvate”. In fact, none of the compounds are indicated as being crystalline and all the compounds of Formula I prepared are purified by column chromatography, not by recrystallization. The specification does not demonstrate that applicant has made any “crystalline form”, “hydrate”, or “solvate” of the instant compounds.
As such, claim 1 should be amended to encompass the compounds of Formula I, stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, only.
Claims 2-15 are rejected for depending upon the limitations of claim 1.
Claims 13-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of cancers mediated by ROS1, NTRK, and ALK and drug-resistant mutations thereof, does not reasonably provide enablement for treatment or prevention of all diseases mediated by ROS1, NTRK, and ALK and drug-resistant kinases thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make use of the invention commensurate in scope with these claims.
The applicant’s attention is drawn to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1998), where the court set forth eight factors to considers when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the examples; and (8) the quantity of experimentation necessary.
Breadth of Claims
Claim 13 broadly encompasses a method of treating or preventing any disease mediated by ROS1, NTRK, and ALK and drug-resistant kinases thereof (page 21, lines 23-25 of the spec. says the instant invention can be used to treat and prevent inflammation, cancer, cardiovascular disease, infection, immunological disease, metabolic disease), in any subject in need thereof, comprising administration of any of the compounds of Formula I, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates thereof. Claim 14 mentions these diseases include any cancer, any sarcoma, and any pain (the term “include” is not limiting, see 112(b)). Claim 15 narrows the scope to some cancers.
The term “subject” was not defined in the specification. Accordingly, the broadest reasonable interpretation of the term “subject” is taken to be any animal (humans, other primates, dogs, cats, squid, etc.).
The term “prevention” is not defined in the specification. The Oxford English Dictionary (2024) defines “prevent” as to “preclude the occurrence” and thus claim 13 encompasses embodiments in which the claimed compounds can preclude the many diseases mediated by mediated by ROS1, NTRK, and ALK and drug-resistant kinases thereof. See definition II.9.a. Obtained from oed.com [retrieved on 2025-03-05] URL:httos://www.oed.convdictionary/prevent_y?t=true).
Nature of the invention/ State of the Prior Art/ Predictability in the Art
The art provides no successful method of prevention for all cancers, as taught by Gu et al. (J. Cancer Prev. 25(3): 127-135, 2020) beyond: (i) eliminating or mitigating risk factors by adopting healthy behaviors and lifestyles, such as avoiding tobacco, alcohol, and UV radiation; (ii) screening to identify precancerous lesions and taking intervention measures to prevent disease progression to malignancy; or (iii) controlling the symptoms or morbidity caused by cancer therapy. Gu also recommends that high-risk populations take chemo-preventive agents such as selective estrogen receptor modulators for breast cancer, and non-steroidal anti-inflammatory drugs (aspirin) for colorectal cancer prevention etc. There is not one single drug that works for the prevention of all cancers.
Finally, the medical arts are also generally considered to be unpredictable making the goal of achieving prevention in this case even less likely. See Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). See also In re Fisher, 427, F. 2d 833, 166, USPQ 18 (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 involve.”).
Level of One of Ordinary Skill
The level of one of ordinary skill in the art would be high, likely an M.D. or Ph.D. in the medical arts (e.g., studying treatment of cancers). See Orthopedic Equip. Co. v. All Orthopedic Appliances, Inc., 707 F.2d 1376 at 1381–82 (Fed. Cir. 1983) (Factors that may be considered in determining level of ordinary skill in the art include: … type of problems encountered in the art …”).
Guidance/Working Examples
The specification discloses in vitro studies of ROS1, TRKA, ALK, ROS1(G2032R), TRKA(G677C), and ALK(G1202R) inhibition with some of the instant compounds (Table 2, page 40). Table 3 (page 42) shows inhibition of additional drug-resistant mutant Ba/F3 cell lines in order to study inhibition of cell proliferation by compounds. Test Example 3 shows in vivo tumor volume growth inhibition after administration of one of the instant compounds to mice after being inoculated with cancer cells (Table 5).
Thus, the specification provides no evidence of treatment or prevention of all diseases related to ROS1, TRKA, ALK, or drug-resistant kinases thereof.
Degree of Experimentation
To practice the invention as claimed, the skilled artisan would have to screen each of the many compounds encompassed by the broad genus in instant Formula I, in order to determine whether the compounds meet the functional limitations of the claim for the treatment and prevention of any diseases related to ROS1, TRKA, ALK, or drug-resistant kinases thereof, including cancers. In addition, the skilled artisan would need to determine which subjects would benefit from treatment and prevention of these diseases (humans, other primates, cats, dogs, squid, etc.) by administering the instantly claimed compounds to a statistically significant pool of subjects from each species. Prevention the aforementioned conditions would require long-term monitoring of each patient for appearance of any new diseases related to ROS1, TRKA, ALK, or drug-resistant kinases thereof. Thus, the quantity of experimentation in this area would be extremely large, since there are a significant number of parameters that would have to be studied beyond the preliminary in vitro and in vivo studies, which enable only the treatment of cancers related to ROS1, TRKA, ALK, or drug-resistant mutations thereof. Furthermore, the ultimate outcome of such experimentation is completely unpredictable.
In sum, taking into consideration the Wands factors outlined above, an undue amount of experimentation would be required here to make and use the full scope of the claimed 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 13-15 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.
Claim 13 states: “ROS1, NTRK, and ALK and drug-resistant kinases thereof”. It is unclear if Applicant intends drug-resistant kinases of ALK only, or drug-resistant kinases of ROS1, NTRK, and ALK. Furthermore, the specification seems to refer to drug-resistant mutations not kinases (see objection to the spec.). The specification does not define “mutations” as “kinases”. Therefore, in light of the spec. (see Table 2, page 40) Examiner believes Applicant intended to claim treatment of “diseases related to pathological characteristics mediated by ROS1, NTRK, and ALK, and drug-resistant mutations of ROS1, NTRK, and ALK” – claim will be interpreted as such.
Regarding claim 14, the term "include" renders the claim indefinite because it is unclear whether the limitation(s) following the term are part of the claimed invention. See MPEP § 2173.05(d).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 14 recites the broad recitation “cancer”, and the claim also recites “sarcoma” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 15 is rejected for depending upon the limitations of claim 14.
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 1-2, 5, 7-8, 10-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-11 of US Patent No.12,435,089 (US ‘089); in view of Meanwell et al. (J. Med. Chem. 2011, 54, 2529–2591) (“Meanwell”).
Regarding instant claims 1-2, 5, 7-8, 10-12, US ‘089 claims the compounds of Formula I below, wherein ring B can be phenyl or heteroaryl; and Y can be O, NH, or CR1R2, wherein R1-2 can be H or alkyl, thus reading on the instant compounds when instant ring A is
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in view of Meanwell (US ‘089’s claim 1).
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Regarding claim 12, US ‘089 claims a pharmaceutical composition comprising their compounds (US ‘089’s claim 8).
Regarding claim 13-15, US ‘089 claims methods of treating diseases mediated by ROS1, NTRK, and ALK, such as cancers, including leukemia (US ‘089’s claims 9-11).
While US ‘089 does not claim their compounds wherein the ring corresponding to instant A is
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, they do claim the instant compounds when the ring corresponding to instant A is
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. The teachings of Meanwell are relied upon to leverage these differences.
Meanwell teaches that the design of bioisosteres frequently introduces structural changes that can be beneficial depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates (abstract). Meanwell teaches -N- and -O- as classical divalent bioisosteres.
Therefore, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they are generically embraced by US ‘089’s disclosed formula in view of Meanwell; In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). See MPEP 2144.08. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of compounds for treating diseases mediated by ROS1, NTRK, and ALK, such as cancers, including leukemia, as disclosed by US ‘089; in view of Meanwell’s teachings that the design of bioisosteres frequently introduces structural changes that can be beneficial in improving lead compounds and drugs, and their disclosure that -N- and -O- are classical divalent bioisosteres. Accordingly, one having ordinary skill in the art would have been motivated with a reasonable expectation of success, to substitute the -N- in US ‘089’s
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ring for -O- to arrive at
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in the instant compounds.
Applicant is advised that similar properties may normally be presumed when compounds are very close in structure. Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Grabiak, 769 F.2d 729, 731, 226 USPQ 870, 871 (Fed. Cir. 1985) (“When chemical compounds have very close structural similarities and similar utilities, without more a prima facie case may be made.”). Thus, evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious. Dillon, 919 F.2d at 697-98, 16 USPQ2d at 1905; In re Wilder, 563 F.2d 457, 461, 195 USPQ 426, 430 (CCPA 1977); In re Linter, 458 F.2d 1013, 1016, 173 USPQ 560, 562 (CCPA 1972) (see MPEP 2144.08(d)).
Response to Arguments
Claims
Claim amendments are acknowledged. No new matter has been introduced.
Allowable Subject Matter/ Claim Objections
Upon further consideration, new rejections have been made over formal matters. Claims 3-4, 6, and 9 remain free of the prior art.
Double Patenting
In view of claim amendments, the NSDP rejection over US ‘089 has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of US ‘089 in view of Meanwell.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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