DETAILED ACTION
Notice of AIA Status
The instant application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the Leahy-Smith America Invents Act (AIA ).
Status of the Claims
The listing of claims filed 8 June 2025 has been examined.
New claims 23–42 are pending. Original claims 1–22 are canceled.
Priority
The instant application was filed 16 April 2022; is a national stage application of PCT/GB2022/052688, filed 21 October 2022, and claims priority to GB 2115150.1, filed 21 October 2021. Applicant’s claim for foreign priority is acknowledged, and a copy of the priority document has been received.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 17 April 2024 is acknowledged and has been considered.
Objections to the Abstract
The abstract of the disclosure is objected to because it recites legal phraseology (“said”) and phrases that can be implied (“The invention relates to”).
Appropriate correction is required.
Examiner recommends changing “said” to “the,” and deleting the implied phrase so the Abstract begins with: “Heterocyclic derivatives and their use . . .”
For guidelines for the preparation of patent abstracts, see MPEP § 608.01(b) (Explaining: The abstract should be in narrative form and avoid legal phraseology (e.g., means, said), terms referring to purported merits of the invention (e.g., new, novel), and phrases that can be implied (e.g., The disclosure concerns, The disclosure defined by this invention). The language should be clear and concise, and not repeat information given in the title. It should not compare the invention with the prior art. The abstract is generally limited to a single paragraph within the range of 50 to 150 words in length.).
Claim Rejections - 35 U.S.C. § 112
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.
Claim 42 is rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 42 is directed to a process of making a compound of formula (I). The process comprises each of steps (a)–(d). Step (e) is optional.
Step (a) reacts a compound of formula (I) with a compound -CO-CH=CHR9 or Y-HetC-CO-CH=CHR9, but does not provide the product of the reaction.
Step (b) reacts a compound of formula (III) with a compound of formula (IV), but does not provide the product of the reaction.
Step (c) recites, “deprotection of a protected derivative of a compound of formula (I).” The term “protected derivative of a compound of formula (I)” is not defined by the claim (e.g., by structure or name). A compound of formula (I) can have numerous functional groups and the claim does not indicate which of those functional groups is protected prior to the deprotection step, or whether numerous functional groups are protected prior to the deprotection step. As such, one of ordinary skill in the art would not be apprised of what compound(s) is/are being deprotected or how the compound(s) is/are deprotected.
Step (d) recites, “interconversion of a compound of formula (I) or protected derivative thereof to a further compound of formula (I) or protected derivative thereof.” The term “protected derivative thereof” is not defined by the claim (e.g., by structure or name). A compound of formula (I) can have numerous functional groups and the claim does not indicate which of those functional groups is protected prior to the step, or whether numerous functional groups are protected prior to the step. As such, one of ordinary skill in the art would not be apprised of what compound(s) is/are being deprotected or how the compound(s) is/are deprotected.
Claim 42 is indefinite because it is unclear what products are provided by the reactions in steps (a) and (b) and how those steps are related to one another to result in a process of making a compound of formula (I). Furthermore, it is unclear what compounds are involved in steps (c) and (d) or how those steps are related to steps (a) and (b) in a process of making a compound of formula (I).
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 112
The following is a quotation 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.
Claims 38–41 are rejected under 35 U.S.C. § 112(a) because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with the claims.
MPEP § 2164.01(a) explains how enablement for the claimed invention can be analyzed:
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” . . . These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The Wands factors are analyzed with respect to the claimed invention in turn below.
The breadth of the claims is broad in scope. Claim 38 recites: “A method for treating an animal for a disease or condition mediated by Polϴ,” which extends to treating an unknown number of diseases for an unidentified population of subjects. Claim 39 recites: “A method for treating an animal for a cancer.” Claims 40 and 41 recite lists of cancers.
The nature of the invention generally relates to the pharmaceutical art and more specifically to a compound of formula I, pharmaceutical compositions thereof, methods of making the compound, and methods of administering the compound to an animal. The compounds exhibit activity as DNA polymerase theta (Polϴ) inhibitors. (Spec., pp.164–167). The specification states: “In vivo studies also show that Polϴ is significantly over-expressed in subjects of HRD ovarian, uterine and breast cancers with associated poor prognosis.” (Id., p.2). Thus, the nature of the invention is sophisticated.
The state of the prior art can be ascertained from the background of the instant specification and articles published contemporaneously with the filing of the instant application. A passage from the instant specification is noted above, and highlights cancers that overexpress Polϴ as a biological target. Chen et al., Genes (2021), 12, 1146 (13 pages) (“Chen”) and Zatreanu et al., Nature Comm. (2021), 12, 3636 (15 pages) (“Zatreanu”) are articles that discuss the potential of Polϴ as a biological target and the drug ART558 as a potential therapeutic. Chen refers to Zatreanu when stating: “[A] recently reported potent and selective Polϴ polymerase (Polϴ-pol) inhibitor developed by Artios Pharma acts additively with PARPi in HR-deficient cells and selectively kills HR-deficient cells as a single agent at low micromolar concentrations.” (Chen, p.4). Chen states: “The recent report on Artios Pharma’s allosteric Polϴ-pol inhibitor class demonstrates for the first time that this specific domain of Polϴ is indeed druggable.” (Id., p.9). Zatreanu states: “ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor.” (Zatreanu, p.1). “As far as we are aware, the discovery of ART558 provides the first evidence that a DNA repair related DNA polymerase can be targeted with a specific small molecule and the synthetic lethality with BRCA1 or BRCA2 provides a rare example of where a synthetic lethality identified via genetic means can be reproduced with a small molecule inhibitor.” (Id., p.8). ART558 appears to be disclosed in WO2021/028643 [IDS].
In view of the disclosures in the specification and relevant articles, the state of the prior art is in its infancy generally, but ascending for treating BRCA1- or BRCA2-cancers. The Brasser Center for BRCA at University of Pennsylvania Medicine (https://www.basser.org/brca) explains BRCA1- or BRCA2-cancers are at heightened risk for breast, ovarian, prostate, and pancreatic cancers.
The level of one of ordinary skill may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
The level of predictability in the art is generally unpredictable. The relevant art requires each potential drug candidate to be assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18, 24 (CCPA 1970). The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement. MPEP § 2164.02(II) explains that a correlation between the claimed invention and the evidence provided in an application, along with a correlation between the evidence and the models recognized in the art, are required:
“Correlation” as used herein refers to the relationship between in vitro or in vivo animal model assays and a disclosed or a claimed method of use. An in vitro or in vivo animal model example in the specification, in effect, constitutes a “working example” if that example “correlates” with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute “working examples.” In this regard, the issue of “correlation” is also dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995) (reversing a USPTO decision based on finding that in vitro data did not support in vivo applications).
Further, treatments may be effective for some subjects and ineffective for other subjects. Thus, each candidate for pharmaceutical or veterinary medicine must be evaluated on its own even when a nexus to an existing drug or class of drugs has been established.
The amount of direction provided by the inventor includes the basis for targeting Polϴ as a biological target in the background section and the therapeutic utility section in the detailed discussion of the invention (Spec., pp.1–2; 20–25). The specification states: “Without being bound by theory it is expected that the Polϴ inhibitors of the present invention will demonstrate certain properties for them to be of particular utility in the therapeutic treatment of certain cancers. For example, in one embodiment, the Polϴ inhibitors of the present invention are suitably lethal in BRCA1 and BRCA2 deficient primary and secondary solid tumours, including breast, ovarian, prostate and pancreas.” (Id., pp. 20–21).
The existence of working examples relate to in vitro assays of the compounds of formula (I) to determine activity as DNA polymerase theta (Polϴ) inhibitors. (Spec., pp.164–167). There are no examples demonstrating in vivo activity against a specific disease.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure is extensive, as it includes in vitro and in vivo screening for each specific disease or disorder encompassed by the claims. As claimed, the indefinite scope of such diseases is essentially unbound.
Scope of Enablement Conclusion
In view of the Wands factors discussed above, the disclosure of the instant application does not reasonably enable a person having ordinary skill in the art to use the full scope of the claimed invention. The breadth of the claims is broad in scope; the nature of the invention is sophisticated; the state of the prior art is in its infancy for treating any disease and ascending for treating specific BRCA1 or BRCA2 cancers; the level of skill in the art is high; the pharmaceutical art is unpredictable; the direction provided by the inventor is consistent with treating specific BRCA1 or BRCA2 cancers; the working examples demonstrate in vitro activity but do not demonstrate in vivo activity consistent with the scope of the claims; and the quantify of experimentation needed to practice the claimed invention is extensive. Thus, when the evidence is considered as a whole, undue experimentation would be required to practice the full scope of the claimed invention.
Examiner recommends canceling claims 38, 40, and 41; and amending claim 39 to recite the treatment of breast, ovarian, prostate, and pancreatic cancers.
Allowable Subject Matter
Claims 23–37 are allowed. The core structure of the compounds of formula (I) (i.e., an amine substituted with a pyridyl and a fused 8-membered-phenyl ring) are not disclosed in the prior art. The closest prior art of record is WO 2021/028643 [IDS], which discloses a compound having a distinct structure that lacks the instantly claimed amine structure.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jason Nolan at (571) 272-2480. The examiner can normally be reached Monday through Friday between 9:00–5:00.
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/JASON M. NOLAN/Patent Examiner, Art Unit 1623
/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621
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