DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-4, 6, 7, 9, 10, 12, 13, 15-20, and 22-24 are pending. Claims 5, 8, 11, 14, 21, 25, and 26 are cancelled. Examiner previously required a restriction (dated September 25, 2025). In response, Applicant elected, without traverse, Group I which encompasses claims 1-4, 6, 7, 9, 10, 12, 13, 15, and 17. Accordingly, claims 16, 18-20, and 22-24 are withdrawn.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/GB2021/053349, filed on December 17, 2021. This application also claims the benefits of Provisional U.S. Application No. 63/126,812, filed on December 17, 2020.
Specification - Abstract
The abstract of the disclosure is objected to because it is not in compliance with 37 C.F.R. 1.72 (b). Specifically, the sheet presenting the abstract includes other parts of the application or other material. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Specification - Disclosure
The disclosure is objected to because of the following informalities:
On pg. 17, lines 23-25, it should read:“As used herein, "treat", "treating" or "treatment" means inhibiting or relieving a disease . For example, treatment can include a postponement of development of the symptoms associated with a disease …”
On pg. 3, within the section describing Figure 1 (lines 10-32), the specification refers to features in Figure 1 as “blue dots” (line 15) and “red dots” (line 18). For clarity and consistency with the figure, Examiner advises to revise the specification to describe these elements in terms appropriate for grayscale (e.g., “black dots” or “grey dots”). Similar revisions should be made for all other color-coded elements that are not distinguishable in the current black-and-white figures.
Appropriate correction is required.
The 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.
Drawings Objection
The drawings are objected as explained below:
The figures appear to have been prepared with color-coding, however, the versions submitted in the application are rendered in gray scale, causing many of the intended color distinctions to appear visually similar. Examiner recommends revising the figures to ensure that the differences between data sets or graphical elements remain discernible in gray scale. This may be accomplished by using distinct shading, patterns (e.g., dashed versus solid lines or speckled versus striped bars), or by clearly labeling each element.
Appropriate correction is required.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 15 and 17 are objected to because of the following informalities:
In claims 15 and 17, “the JMJD6 target compound” should read “the JMJD6 targeting agent” to be consistent with the claim it depends upon (i.e., claim 1).
Appropriate correction is required.
Examiner’s note on novelty and nonobviousness
Novelty:
Liu et al. (Liu) (CN108218854A; published June 29, 2018)
Liu teaches benzopyran-2-ketone compounds used as a JMJD6 inhibitor (see abstract). The JMJD6 targeting agent disclosed in Liu has the following general structure:
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wherein R1 and R2 are defined according to the following:
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(From English-translated document, pg. 6 of 12, table 1, compounds 1-1 [top row], 1-2 [center row], and 1-3 [bottom row]; see top-right corner for page numbers of English-translated document).
The invention described in Liu includes the “use of any compound 1-1, compound 1-2, and compound 1-3 in the phenylpropyran-2-one compounds in the preparation of drugs for the treatment of cancer, the cancer includes lung adenocarcinoma, prostate cancer, Breast cancer, pancreatic cancer, colon cancer, oral squamous cell carcinoma, glioblastoma, etc.” (English-translated document, pg. 4 of 12, paragraph starting with “The use of…”).
Liu discloses that “[s]ince JMJD6 plays a key role in the growth and proliferation of cancer cells and is supported by in vitro enzyme activity experiments, the compounds involved in the present invention [i.e., the benzopyran-2-ketone compounds disclosed by Liu) can be used in medicines for preventing or treating diseases related to JMJD6 inhibitors, especially in medicines for cancer” (English document pg. 5 of 12, last sentence).
However, Liu does not disclose a method of treating endocrine resistant prostate cancer in a subject (i.e., in vivo study) by administering to the subject a JMJD6 targeting agent.
Schofield et al. (Schofield) (US20110130449A1; published June 2, 2011)
Claims 13 and 14 of Schofield are directed towards a method of treating a genetic disorder or cancer, which comprises administering to a subject in need thereof a therapeutically effective amount of a modulator of JMJD6 lysyl hydroxylase activity wherein said modulator is a reported inhibitor of a 2-OG oxygenase other than Jmjd6, or an analogue or variant of such an inhibitor, or an N-oxalyl amino acid such as N-oxalylglycine or a derivative thereof, a glycine or alanine derivative, a 2-oxoacid analogue, a flavonoid or flavonoid derivative such as genistein.
Although the breadth of Schofield’s claims encompasses the instant claim scope, Schofield does not provide any working examples demonstrating treatment of cancer in a subject using a modulator of JMJD6 lysyl hydroxylase activity. Example 10 in Schofield merely reports in vitro inhibition of JMJD6 activity which does not constitute evidence of treating cancer in a subject. The remaining examples disclosed by Schofield are directed to mechanistic and biochemical characterization of JMJD6 (e.g., Example 1: cloning, expression, and purification of human JMJD6; Example 2: identification of JMJD6 interacting proteins; Example 5: identification of site and stereochemistry of hydroxylation by JMJD6; Example 7: specificity of JMJD6) and do not disclose any in vivo cancer treatment data.
Thus, in view of Liu and Schofield, the instant invention corresponding to claims 1-4, 6, 7, 9, 10, 12, 13, 15, and 17 is considered novel.
Nonobviousness:
Prior art referenced:
Zheng et al. (Zheng) (Zheng, H. et al. Jumonji domain-containing 6 (JMJD6) identified as a potential therapeutic target in ovarian cancer. Sig Transduct Target Ther 2019, 4, 24, 1-14.).
The results of an animal study conducted by Zheng “indicated that the SKLB325 [i.e., a JMJD6 inhibitor; see abstract] treatment protocols were effective in suppressing SKOV3, ES2, CP70, and A2780s tumor growth in nude mice” (pg. 10, left col., 1st paragraph, last sentence). In other words, Zheng teaches a method of treating ovarian cancer in a subject by administering to the subject a therapeutically effective amount of a JMJD6 targeting agent. However, Zheng does not teach nor suggest that SKLB325 is capable of treating other cancers, specifically prostate cancer (and more specifically endocrine resistant prostate cancer) in vivo.
Schofield et al. (Schofield) (US20110130449A1; published June 2, 2011)
See the “Novelty” subsection above for the teachings of Schofield.
Although Schofield does not provide any in vivo data demonstrating treatment of cancer in a subject with a modulator of JMJD6 lysyl hydroxylase activity, one of ordinary skill in the art would have been generally motivated to explore whether the JMJD6 modulators could have therapeutic potential in oncology. However, Schofield lists several examples of cancers (e.g., breast or colon cancer, myeloma, or hepatoma) that may be treated by modulating (inhibiting or enhancing) JMJD6 activity (pg. 12, left col., para. 0160, last sentence) without any disclosure or suggestion directed specifically to treat endocrine-resistant prostate cancer in a subject. Moreover, in the absence of any in vivo efficacy data in Schofield, the therapeutic outcome of administering a JMJD6 modulator to treat, specifically, endocrine-resistant prostate cancer in a subject would have been unpredictable and unexpected.
Thus, in view of Zheng and Schofield, the instant invention corresponding to claims 1-4, 6, 7, 9, 10, 12, 13, 15, and 17 is considered nonobvious.
Claim Rejections – Improper Markush Grouping
Claims 1-4, 6, 7, 9, 10, 12, 13, 15, and 17 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
A Markush claim contains an “improper Markush grouping” if: (1) the species of the Markush group do not share a single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a "single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the Specification or known in the art to be functionally equivalent (see Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, p. 7166, left and middle columns, bridging paragraph).
The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons:
Depicted below are specific examples of JMJD6 targeting agents from the prior art:
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Zheng et al. (Zheng) (Zheng, H. et al. Jumonji domain-containing 6 (JMJD6) identified as a potential therapeutic target in ovarian cancer. Sig Transduct Target Ther 2019, 4, 24, 1-14.; see Fig. 3a).
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wherein R1 and R2 are defined according to the following:
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Liu et al. (Liu) (CN108218854A; published June 29, 2018); From English-translated document, pg. 6 of 12, table 1, compounds 1-1 [top row], 1-2 [center row], and 1-3 [bottom row].
The four compounds depicted above are all reported to be JMJD6 inhibitors (i.e., JMJD6 targeting agents). However, the compound disclosed in Zheng and the compounds disclosed in Liu each possesses a distinct core chemical scaffold with no common structural features readily apparent among them. Claim 3 further recites that the JMJD6 targeting agent of claim 1 is a small molecule inhibitor, or an antibody or fragment thereof.
As demonstrated above, even within the category of small-molecule JMJD6 inhibitors, there exists substantial structural diversity. Claim 3 expands the scope further to include additional structurally distinct classes of agents including antibodies or fragments thereof which bear no discernable structural similarity to small-molecule JMJD6 inhibitors. Because the recited alternatives lack a shared structural feature, claims 1 and 3 are, therefore, rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives.
Claims 2-4, 6, 7, 9, 10, 12, 13, 15, and 17, which are dependent on claim 1, are also rejected for further requiring and/or reciting the improper Markush grouping of claim 1.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. § 134 and 37 CFR41.31 (a) (1) (emphasis provided).
Claim Rejections - 35 USC § 112(a)
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 1-4, 6, 7, 9, 10, 12, 13, 15, and 17 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention relates to methods for treating prostate cancer by targeting the generation of splice variants of the androgen receptor. In one aspect, this can be achieved by targeting JMJD6 to reduce the production of androgen receptor splice variants. The invention finds particular use in the treatment of prostate cancer that is resistant to conventional androgen therapy.
State of the prior art
See “Examiner’s note on novelty and nonobviousness” section above.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in oncology and/or medicinal chemistry and would be familiar with standard methods for evaluating therapeutic efficacy.
The presence or absence of working examples
In the instant specification, the “terms ‘treat,’ ‘treating’ or ‘treatment’ means inhibiting or relieving a disease... For example, treatment can include a postponement of development of the symptoms associated with a disease… and/or a reduction in the severity of such symptoms that will, or are expected, to develop with said disease. The terms include ameliorating existing symptoms, preventing additional symptoms, and ameliorating or preventing the underlying causes of such symptoms. Thus, the terms denote that a beneficial result is being conferred on at least some of the mammals, e.g., human patients, being treated” (pg. 17, lines 23-29). In the instant specification, the term “subject” refers to an animal which is the object of treatment, observation, or experiment (pg. 17, lines 32-33).
Instant claims 1-4, 6, 7, 9, 10, 12, 13, 15, and 17 are directed towards a method for treating or preventing endocrine resistant prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a JMJD6 targeting agent. Based on the definition of “treating” and “subject” as discussed above, the instant specification, therefore, must show working examples of endocrine resistant prostate cancer being treated (e.g., a cancerous tumor decreasing in volume within mice) in vivo.
The instant specification (pg. 32, lines 30-37 and pg. 33, lines 1-5) only discloses results from in vitro studies (i.e., pyridine-2,4-dicarboxylic acid [2,4-PDCA] inhibits JMJD6 in 22Rv1 prostate cancer [i.e., PC] cells) and, therefore, the findings from the in vitro studies cannot enable instant claims 1-4, 6, 7, 9, 10, 12, 13, 15, and 17 since the claims are directed towards a method of treating endocrine resistant prostate cancer in a subject. Further, the instant specification provides no evidence that endocrine resistant prostate cancer was completely prevented in a subject nor does it provide any working examples of a subject also being administered a further anti-cancer therapy.
The instant specification also states:
“[W]e employed 2,4-PDCA to provide 'proof-of-principle' evidence that PC cell inhibition of JMJD6 by an active site binding inhibitor is possible and impacts on AR-V7 protein levels. We appreciate that 2,4-PDCA is not optimised for therapeutic use and that such optimisation has been reported for inhibitors of other 2OG oxygenases, e.g. the hypoxia inducible factor prolyl hydroxylases. Thus, at least in some cell types, the permeability of 2,4-PDCA is low, with high concentrations being required to elicit its effects in vitro [55, 56]. 2,4-PDCA itself is thus unlikely to be useful for in vivo studies. Furthermore, 2,4- PDCA is a broad-spectrum 2OG dioxygenase inhibitor and may inhibit other 2OG oxygenases, including JmjC-domain containing proteins. Selectivity can be achieved (and potency increased) by screening JMJD6 inhibitors against other 2OG oxygenases coupled with variation of non-optimal inhibitor compounds by structure activity relationship studies” (pg. 35, lines 24-34).
While Examiner acknowledges the significance of the studies presented and agrees that the described findings are scientifically important, the specification does not enable a method for treating or preventing endocrine resistant prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a JMJD6 targeting agent. As stated above, this is because the application provides no in vivo data demonstrating therapeutic efficacy of a JMJD6 targeting agent in any animal model. Further, for the one compound evaluated in vitro (i.e., 2,4-PDCA), the instant specification expressly states that the compound is unlikely to be useful for in vivo studies due to its low permeability and the need for high concentrations to achieve activity in vitro (pg. 35, lines 28-30).
The amount of direction or guidance present and quantity of experimentation necessary
Although the specification states that JMJD6 inhibitors could be made more selective and more potent by “screening JMJD6 inhibitors against other 2OG [i.e., 2-oxoglutarate] oxygenases coupled with variation of non-optimal inhibitor compounds by structure activity relationship studies” (pg. 35, lines 32-34), the disclosure provides no guidance regarding a core scaffold from which such inhibitors might be developed, nor does it describe any structure-activity relationship data or methodology. In the absence of such direction, a person of ordinary skill in the art would require undue experimentation to:
Identify a suitable JMJD6 inhibitor AND
To evaluate their efficacy in vivo.
The breadth of the claims
According to the instant specification, a “JMJD6 targeting agent” encompasses any agent capable of targeting either the JMJD6 gene or the JMJD6 protein (pg. 9, lines 31-35). Accordingly, the claims are broad insofar as the instant claims are directed towards a method for treating or preventing endocrine resistant prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of a JMJD6 targeting agent without imposing any structural limitations on the agent. Thus, the claims could encompass compounds or materials of essentially any chemical structure, provided they can target JMJD6, thereby rendering the scope of the claimed therapeutic agents exceedingly broad.
Claim Rejections - 35 USC § 112(b)
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 6, 7, 9, 10, and 13 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 6 recites “a mimic, variant or competitor of the 2OG (2-oxoglutarate) JMJD6 co-substrate.” While the specification does disclose examples of mimics of 2OG (pg. 11, lines 26-34), the specification does not limit the mimics or variants of 2OG to those explicitly listed in the specification. Further, the terms “mimic” and “variant” are not defined in the specification and, therefore, can comprise of numerous compounds with structures that can potentially vary significantly from the structure of 2OG. Thus, claim 6 is rendered vague and indefinite.
Claim 7 recites “a pyridine-carboxylate derivative, or N-oxalyl amino acid derivative, or succinate derivative, or 2OG or 2-oxo acid derivative.” The term “derivative” is not defined in the specification and, therefore, can comprise of numerous compounds with structures that can potentially vary significantly from the structure of pyridine-carboxylate, N-oxalyl amino acid, succinate, or 2OG. Thus, claim 7 is rendered vague and indefinite.
Claim 7 further recites “optionally wherein the JMJD6 targeting agent comprises pyridine-2,4-dicarboxylic acid.” However, this limitation is inconsistent with the teachings of the instant specification which expressly states that pyridine-2,4-dicarboxylic acid is unlikely to be useful for in vivo studies due to its low permeability and the need for high concentrations to achieve activity in vitro (pg. 35, lines 28-30). The instant specification therefore suggests that pyridine-2,4-dicarboxylic acid is not a suitable JMJD6 targeting agent for treating endocrine resistant prostate cancer in a subject. This contradiction between the claim language and the specification creates uncertainty as to the scope of the invention. It is unclear whether the Applicant intends to include or exclude pyridine-2,4-dicarboxylic acid as a viable therapeutic agent in the claimed method. Accordingly, the claim is rendered indefinite because one of ordinary skill in the art cannot ascertain the metes and bounds of the claimed invention with reasonable certainty.
Regarding claims 9 and 13, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 10, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624