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, 10, 12, 13, 15-20, 22-24, and 27-29 are pending. Claims 5, 8, 9, 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 now encompasses claims 1-4, 6, 7, 10, 12, 13, 15, 17, and 27-29. Accordingly, claims 16, 18-20, and 22-24 are withdrawn.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.
Withdrawn Rejections
Applicant is notified that any outstanding rejection or objection that is not expressly maintained in this office action has been withdrawn or rendered moot in view of applicant’s amendments and/or remarks.
Specification - Disclosure
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.
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:
PNG
media_image1.png
106
261
media_image1.png
Greyscale
wherein R1 and R2 are defined according to the following:
PNG
media_image2.png
494
582
media_image2.png
Greyscale
(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, specifically, 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 (including, specifically, endocrine-resistant prostate 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, 10, 12, 13, 15, 17, and 27-29 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, 10, 12, 13, 15, 17, and 27-29 is considered nonobvious.
------------------------------------ Maintained Rejections ------------------------------------
Claim Rejections – Improper Markush Grouping
Claim 3 is 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:
Claim 3 recites that the JMJD6 targeting agent of claim 1 is a small molecule inhibitor, or an antibody or fragment thereof.
Depicted below are specific examples of small molecule JMJD6 targeting agents from the prior art:
PNG
media_image3.png
364
591
media_image3.png
Greyscale
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).
PNG
media_image1.png
106
261
media_image1.png
Greyscale
wherein R1 and R2 are defined according to the following:
PNG
media_image4.png
475
559
media_image4.png
Greyscale
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 small molecule 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. Each of the distinct core structures belong to a different physical or chemical class.
Further, in Applicant Remarks dated April 14, 2026, Applicant asserts that:
“[C]laim 3 is not directed to a group consisting of alternative members. Claim 3 is directed to a “small molecule inhibitor.” The “antibody or fragment thereof,” recitation refers to an “antibody or fragment” of the small molecule inhibitor recited in the claim, and are thus not alternative members of any alleged group of JMJD6 targeting agents, even if such a group were present in the claim, which Applicant submits it is not. Thus, claim 3 is not directed to a group consisting of alternative members, and is not a Markush claim” (pg. 10 of 22).
Examiner does not find Applicant’s arguments persuasive for the following reasons:
Claim 3 is directed to a group consisting of alternative members.
According to the instant specification:
“In an embodiment the targeting agent may be a small molecule inhibitor or a biomacromolecule such as an antibody or a fragment thereof… The small molecule inhibitor or the antibody may bind in a manner which blocks the catalytic activity of JMJD6 protein” (pg. 9, lines 35-36 and 38-39).
The instant specification clearly states that the JMJD6 targeting agent can be a small molecule inhibitor or an antibody (two alternatives) and the “fragment thereof” is referring to a fragment of the antibody.
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, claim 3 is, therefore, rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives.
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.
Enablement
Claims 1-4, 6, 7, 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 and the predictability or lack thereof in the art
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 has established a correlation between in vitro JMJD6 inhibition and in vivo efficacy for ovarian cancer. However, such findings are limited to ovarian cancer and do not establish that JMJD6 is a recognized or predictive therapeutic target for endocrine-resistant prostate cancer.
Prior art referenced:
Wong et al. (Wong) (Wong, M. et al. JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma. Nature Communications 2019, 10, 3319.).
Wong teaches the following:
“Knocking down JMJD6 reduces neuroblastoma cell proliferation and survival in vitro and tumor progression in mice… Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice” (abstract). The JMJD6 targeting agent in this case is a shRNA that is used to inhibit the expression of the JMJD6 gene (pg. 7, right col., “JMJD6 is important for neuroblastoma progression in vivo” section, 1st sentence).
In other words, Wong has established a correlation between in vitro effects on cell proliferation and survival and reduced tumor progression in vivo within the context of neuroblastoma. However, such findings are limited to neuroblastoma and do not establish that JMJD6 is a recognized or predictive therapeutic target for endocrine-resistant prostate cancer.
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 as well as organic synthesis and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
The presence or absence of working examples
The instant specification only discloses results from in vitro studies:
pyridine-2,4-dicarboxylic acid [2,4-PDCA] inhibits JMJD6 in 22Rv1 prostate cancer cells (pg. 32, lines 23-29) and
“Treatment with JMJD6 siRNA (25 nM) resulted in a significant reduction in the growth of the castration-resistant AR-V7-expressing PC cell lines LNCaP95 and 22Rv1, as evidence by a reduction in cell number, compared to treatment with non-targeting control siRNA (25 nM) (FIG. 3A). The growth of androgen-sensitive LNCaP cells was also significantly inhibited by JMJD6 siRNA knockdown” (pg. 29, Example 3, lines 30-37).
The instant specification does not establish a correlation between in vitro JMJD6 inhibition and in vivo efficacy for endocrine resistant prostate cancer.
The instant specification does not establish a correlation between in vitro JMJD6 inhibition and prevention of endocrine resistant prostate cancer in vivo.
The instant specification provides no evidence or working examples 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 breadth of the claims
According to the instant specification and instant claim 1, a “JMJD6 targeting agent” encompasses an agent which modulates the catalytic activity and/or biological function/activity of the JMJD6 protein or the expression of the JMJD6 gene (pg. 9, lines 30-31). 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 agent exceedingly broad.
The amount of direction or guidance present; andthe quantity of experimentation needed to make and use the invention based on the content of the disclosure
The instant specification, while enabling for in vitro use of JMJD6 targeting agents that modulate the catalytic activity and/or biological function of JMJD6 protein or inhibit expression of the JMJD6 gene (via antisense oligonucleotides or RNAi mediators), is not enabling for the claimed method as recited in instant claim 1.
In Applicant Remarks (dated April 14, 2026; pg. 16 of 22), Applicant states that since other JMJD6 inhibitors are known and the 2-oxoglutarate (2OG) mimic (i.e., pyridine-2,4-dicarboxylic acid [abbreviated as: 2,4-PDCA]) was used in the instant specification as a JMJD6 inhibitor in cell-based assays with a human prostate carcinoma epithelial cell line, these JMJD6 inhibitors can be identified and tested without undue experimentation. However, the instant claims are not limited to known JMJD6 inhibitors and, instead, encompass any JMJD6 target agent, including agents of any chemical structure (see “5. The breadth of the claims” section above) that satisfies limitations (a) and (b) as stated in instant claim 1. From what Examiner found in the prior art, the prior art does not establish a correlation between in vitro JMJD6 inhibition and in vivo efficacy for endocrine resistant prostate cancer. In the absence of such a correlation, a person of ordinary skill in the art would not reasonably expect that all JMJD6 inhibitors that demonstrate in vitro activity would necessarily be effective in treating endocrine resistant prostate cancer in a subject.
In Applicant Remarks (dated April 14, 2026), Applicant further states:
“As a preliminary matter, it is well-accepted in the art that in vitro data is predictive of in vivo results and that many pharmaceutical patents have been allowed on the basis of in vitro data only. Applicant further submits that the description and examples presented in the instant application sufficiently correlate the disclosed in vitro utility and in vivo activity” (pg. 18 of 22).
Applicant also refers to MPEP 2164.02(II) regarding the correlation between in vitro utility and in vivo activity.
Examiner has reviewed MPEP 2164.02(II) and reproduced the section below:
II. CORRELATION: IN VITRO/IN VIVO [AltContent: rect]
The issue of "correlation" is related to the issue of the presence or absence of working examples. "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).[AltContent: rect]
Since the initial burden is on the examiner to give reasons for the lack of enablement, the examiner must also give reasons for a conclusion of lack of correlation for an in vitro or in vivo animal model example. However, a rigorous or an invariable exact correlation is not required, as stated in Cross v. Iizuka, 753 F.2d 1040, 1050, 224 USPQ 739, 747 (Fed. Cir. 1985):[AltContent: rect]
[B]ased upon the relevant evidence as a whole, there is a reasonable correlation between the disclosed in vitro utility and an in vivo activity, and therefore a rigorous correlation is not necessary where the disclosure of pharmacological activity is reasonable based upon the probative evidence. (Citations omitted.)[AltContent: rect]
Below are Examiner’s response to Applicant’s arguments using MPEP 2164.02(II):
“…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.”
From what Examiner found in the prior art, the prior art does not establish a correlation between in vitro JMJD6 inhibition and in vivo efficacy for endocrine resistant prostate cancer.
Examiner also has evidence that not all in vitro JMJD6 inhibition would correlate to in vivo efficacy for endocrine resistant prostate cancer. This evidence was provided by the instant specification:
“[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 10-18).
“However, a rigorous or an invariable exact correlation is not required.”
While it is recognized that a rigorous or invariable exact correlation between in vitro and in vivo results is not required, such principle applies only where the model is accepted as reasonably predictive of the claimed condition.
In the present case, neither the prior art nor the instant specification establishes that inhibition of JMJD6 in vitro is predictive of therapeutic efficacy in endocrine-resistant prostate cancer in vivo.
As stated previously, the instant specification itself acknowledges that the exemplified inhibitor, 2,4-PDCA, is unlikely to be useful in vivo, further providing evidence that the disclosed in vitro activity does not reliably translate to in vivo efficacy.
Even though:
Applicant states that other JMJD6 inhibitors are known and a POSITA could test these known JMJD6 inhibitors without undue experimentation, and
Applicant states that an example may be “working” or “prophetic” (see MPEP 2164.02) ,
the instant specification does not demonstrate that any of the known JMJD6 inhibitors is effective in vivo to begin with.
As such, examiner is not persuaded that the in vitro JMJD6 inhibition as disclosed in the instant specification correlates with in vivo efficacy for endocrine resistant prostate cancer.
Further, the disclosure relies heavily on forward-looking and speculative language, for example, stating that “Our demonstration that inhibition of JMJD6 by a broad-spectrum 2OG oxygenase inhibitor (that is an active site binding 2OG competitor) downregulates AR-V7 levels should promote the pursuit of more potent and selective JMJD6 inhibitors in future drug discovery efforts” (pg. 34, lines 7-10), which emphasizes that the instant specification contemplates a future research program rather than providing a presently enabled therapeutic method.
Applicant also made a note “that many pharmaceutical patents have been allowed on the basis of in vitro data only” (pg. 18 of 22).
Examiner is not relying on other pharmaceutical patents and, instead, relies on the MPEP for information regarding the correlation between in vitro and in vivo data as described above.
Furthermore, although the specification suggests the use of 2OG mimics, variants thereof, or pyridine-carboxylate derivatives, it fails to provide structurally defined classes, general formulas, or guidance regarding substituent selection that would enable a skilled artisan to identify operative compounds. The specification does not disclose which structural features are required to achieve JMJD6 inhibition in a therapeutically relevant context (specifically for treating endocrine resistant prostate cancer), nor does it provide direction for optimizing compounds to possess suitable pharmacological properties for in vivo use. As a result, a skilled artisan would be required to engage in undue experimentation to determine which specific compounds, including which substituents or modifications to 2OG mimics or pyridine-carboxylate derivatives, would yield compounds capable of producing the claimed in vivo therapeutic effect.
Accordingly, the issue is not one of imperfect in vitro-in vivo correlation, but rather the absence of a recognized or reliable correlation, coupled with the lack of any demonstrated in vivo efficacy, such that a person of ordinary skill in the art would not reasonably expect the claimed therapeutic effect without undue experimentation.
Additionally, the instant specification does not provide long-term studies demonstrating that administration of a JMJD6 targeting agent prevents the development of endocrine-resistant prostate cancer in a subject. Nor does the specification provide a mechanistic or predictive framework that would allow a POSITA to reasonably conclude that inhibition of JMJD6 would prevent disease onset. Demonstrating prevention of a disease requires longitudinal, time-dependent studies in which subjects are monitored over an extended period to establish that administration of the claimed agent reduces the incidence or onset of the disease relative to an appropriate control. Thus, such studies would involve undue experimentation and cannot be reasonably inferred from short-term in vitro assays that also currently have no correlation to in vivo efficacy.
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 and 7 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.
Regarding claim 6:
Claim 6 recites “a mimic, variant or competitor of the 2OG (2-oxoglutarate) JMJD6 co-substrate.”
Applicant submits that “the meaning and basic structure of a ‘mimic of 2OG’ is defined in the specification and examples provided, at least in page 11 of the Application, the metes and bounds of what constitutes mimics or variants of 2OG would be clear to a skilled person reading the specification” (pg. 20 of 22).
While the specification does disclose examples of mimics of 2OG (pg. 11, lines 19-27) and provides the structure of 2OG (pg. 11, lines 17-18), 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. The specification explicitly states: “A mimic of 2OG may have structural or steric similarities to 2OG” (pg. 11, lines 15-16). This statement also means that a mimic of 2OG also may not have structural or steric similarities to 2OG. Therefore, a “mimic” or “variant” of 2OG 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.
Regarding claim 7:
Claim 7 recites “a pyridine-carboxylate derivative, or N-oxalyl amino acid derivative, or succinate derivative, or 2OG or 2-oxo acid derivative.”
Applicant asserts that “the meaning of the term ‘derivative’ is clear to a skilled person in the art reading the specification. A skilled person in the art understands that a derivative is something that is formed from a precursor through some sort of modification” (pg. 21 of 22).
However, the specification does not provide any objective boundaries or structural limitations that would inform a skilled artisan as to the scope of such derivatives. Specifically, the specification states that a “mimic of 2OG may have structural or steric similarities to 2OG” (pg. 11, lines 15-16) which does not require that such similarities be present. Thus, the definition of a “mimic” encompasses compounds that may lack structural or steric resemblance to 2OG altogether. The specification further identifies pyridine-carboxylate derivatives, for instance, as examples of such mimics, yet does not define the structural features that would qualify a given derivative as falling within the scope of the invention.
Since the term “derivative” is used without any limiting structural criteria, and because the specification permits inclusion of compounds that may not share meaningful structural similarity with either 2OG or pyridine-carboxylate, the scope of the term “derivative” is effectively open-ended. As a result, a person of ordinary skill in the art would not be able to determine, with reasonable certainty, which compounds fall within the scope of claim 7. Accordingly, the metes and bounds of the claim cannot be ascertain and claim 7 is rendered vague and indefinite.
------------------------------------ Added Rejections ------------------------------------
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.
Written Description
Claims 1-4, 6, 7, 10, 12, 13, 15, 17, and 27-29 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.
According to MPEP § 2163:
“Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’ See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).
As stated above in the “Enablement” section – “5. The breadth of the claims” subsection from “Maintained Rejections,” 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 agent exceedingly broad.
Even though:
Claim 4 limits the JMJD6 targeting agent to a substrate or 2OG (2-oxoglutarate) or dioxygen co-substrate competitive inhibitor, a non-competitive inhibitor or an un-competitive inhibitor,
claim 6 limits the JMJD6 targeting agent to a compound which is a mimic, variant or competitor of 2OG, and
claim 7 limits the targeting agent to a pyridine-carboxylate derivative, N-oxalyl amino acid derivative, succinate derivative, or 2OG or 2-oxo acid derivative,
this genus is still considered very broad. The specification states that a “mimic of 2OG may have structural or steric similarities to 2OG” (pg. 11, lines 15-16). Thus, the definition of a “mimic” encompasses compounds that may also lack structural or steric resemblance to 2OG altogether. The specification further identifies pyridine-carboxylate derivatives, for instance, as examples of such mimics, yet does not define the structural features that would qualify a given derivative as falling within the scope of the invention. Since the term “derivative” is used without any limiting structural criteria, and because the specification permits inclusion of compounds that may not share meaningful structural similarity with either 2OG or pyridine-carboxylate, the scope of the claimed “derivative” is effectively open-ended and encompasses a very broad scope of compounds.
Despite this breadth, the specification relies on essentially a single small molecule species, 2,4-PDCA, to represent this structurally diverse genus. Additionally, the specification does not have a working example of using an antibody or fragment thereof as the JMJD6 targeting agent. Thus, the specification does not provide representative species spanning the full breadth of the claimed genus and fails to provide written description support that inventors were in possession of the full scope of the invention.
Moreover, the disclosure of 2,4-PDCA being unsuitable for in vivo (pg. 35, lines 10-18) use further undermines any assertion that the inventors were in possession of the full scope of 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 target agent as recited in instant claim 1.
With respect to instant claim 27, the claim recites that the antisense oligonucleotide or RNAi mediator may be selected from siRNA, shRNA, or “another nucleotide molecule,” thereby encompassing a broad genus of nucleotide-based agents. However, the specification provides only a limited number of examples within this genus, namely siRNA-mediated knockdown of JMJD6 in vitro (pg. 29, Example 3, lines 30-37), and does not disclose any working examples or representative species of “another nucleotide molecule” (note: shRNA-mediated knockdown of JMJD6 was shown in the prior art; see “Enablement” section of “Maintained Rejections” – “2. State of the prior art and the predictability or lack thereof in the art” subsection, Wong reference). Thus, the specification does not provide representative species spanning the full breadth of the claimed genus and fails to provide written description support that inventors were in possession of the full scope of the claimed invention.
Additionally, neither the instant specification nor the prior art establishes a correlation between in vitro JMJD6 inhibition and in vivo efficacy for endocrine resistant prostate cancer (see “Enablement” section of “Maintained Rejections” – “2. State of the prior art and the predictability or lack thereof in the art” subsection for details). Therefore, in vitro JMJD6 inhibition translating to in vivo efficacy for endocrine resistant prostate cancer is currently unpredictable.
Furthermore, the instant specification does not provide long-term studies demonstrating that administration of a JMJD6 targeting agent prevents the development of endocrine-resistant prostate cancer in a subject. Nor does the specification provide a mechanistic or predictive framework that would allow a POSITA to reasonably conclude that inhibition of JMJD6 would prevent disease onset. Demonstrating prevention of a disease requires longitudinal, time-dependent studies in which subjects are monitored over an extended period to establish that administration of the claimed agent reduces the incidence or onset of the disease relative to an appropriate control. Thus, such studies cannot be reasonably inferred from short-term in vitro assays that also currently have no correlation to in vivo efficacy and the instant specification fails to provide written description support that inventors were in possession of a method for preventing endocrine resistant prostate cancer in a subject as recited in instant claim 1.
Claims 2-4, 6, 7, 10, 12, 13, 15, 17, and 27-29, which are dependent on claim 1, are also rejected for further requiring and/or reciting limitations that do not have written description support.
---------------------------- Rejections necessitated by the amended claims ----------------------------
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.
Enablement
Claims 27-29 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.
See “Enablement” subsection within the “Maintained Rejections” section above for details on the Wands Factors.
Claims 27-29, which are dependent on claim 1, are also rejected for further requiring and/or reciting the non-enabling limitations of claim 1.
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.
Claim 29 is 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.
Regarding claim 29:
Claim 29 recites, “wherein the further anti-cancer therapy is selected from abiraterone/abiraterone acetate, enzalutamide or apalutamide.” Claim 29 is dependent on claim 1 which does not mention an anti-cancer therapy. Thus, there is insufficient antecedent basis for this limitation in the claim.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY H. MURRAY can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
Prosecution Insights