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 .
DETAILED ACTION
Claims 1-6, 16, 19, 21-25, and 27-32 are pending in the instant application.
Claims 1-6, 16, 19, 21-25, and 27-32 are examined herein.
Priority
The instant application claims benefit of priority to U.S. Provisional Application No. 63/252,995, filed on 06 October 2021, and PCT/US2022/045895, filed on 06 October 2022. The claims to the benefit of priority are acknowledged. As such, the effective filing date of the claims is 06 October 2021.
Information Disclosure Statement
The information disclosure statement (IDS), submitted on 02 April 2024, is acknowledged and considered. The submissions are in compliance with the provisions of 37 CFR 1.97.
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, 4-6, 16, 19, 21-25, and 27-32 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 lung cancer, pancreatic cancer, cancer with MTAP gene deletion, and cancer with CDKN2A gene deletion, fails to provide the required enablement for treatment of all cancer. 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 these claims.
The instant claims are drawn to the method of treating cancer comprising administering a taxane and the PRMT5 inhibitor of claim 1. The specification fails to provide information that would allow the one skilled in the art to practice treating all cancer.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth the eight factors to consider 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:
the nature of the invention
the state of the prior art
the predictability of the art
the amount of direction or guidance provided
the presence or absence of working examples
the breadth of the claims
the quantity of experimentation necessary
the relative skill of those in the art
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention - is a method of treating cancer comprising administering a taxane and the PRMT5 inhibitor of claim 1.
The state of the prior art - the pharmacological art requires the screening of potential drug candidates in vitro and in vivo to determine if the drug candidates exhibit the desired pharmacological activities.
In order to treat a disease: one would need to precisely identify what the disease is, identify what biological target is connected with the disease, demonstrate that the drug candidate in some way modulates the normal processes of the biological target, and demonstrate that a patient benefited from such modification without detrimental side effects. Typically, this process includes in vitro laboratory screening, preclinical in vivo screening, and three phases of clinical trials. Once this arduous process has been successfully completed by a drug candidate, subsequent drug candidates will benefit from the established proof of concept. The subsequent drug candidates must demonstrate a substantial correlation between their biological activity and that of the known drug candidate.
In the instant case, the prior arts recognize that therapeutic agents have potential to exhibit antagonistic property toward PRMT5, which can be used to treat MTAP-deleted cancers (Song et al. Genes Dis. 2025;13(1):101796)
The predictability or unpredictability of the art – the law recognizes the pharmaceutical art as an unpredictable art and requires each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18 24 (CCPA 1970). Accordingly, the more unpredictable an area is the more specific disclosure is necessary in order to satisfy the statute. Section 2164.02 of the MPEP provides:
"[C]orrelation” as used herein refers to the relationship between in vitro and in
vivo animal model assays and a disclosed or a claimed method of use . . . 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.
In light of these remarks, the Examiner finds that one of ordinary skill in the art would agree with the court; that is, the pharmaceutical art is unpredictable. Thus, a substantial correlation is necessary for establishing the potential of new therapeutics.
Additionally, within pharmaceutics, the art of cancer therapeutics is well known to be unpredictable due to the differing etiologies and mechanisms of action for particular cancers. There are more than 200 known cancers; treatment applicable to one is unlikely to be applicable to another. Bianchi et al. (Current Opinion in Cell Biology. 2020; 63:135-143) attributes this unpredictability to tissue specificity, noting most cancer driver genes are mutated in a tissue-dependent manner, which affects therapeutic response (page 135). For example, BRAF inhibition is an effective therapy for BRAF-mutated melanomas, but not BRAF-mutated colon cancer (page 140); same mutation, different tumors, therefore different therapeutic outcomes. Therefore, from the well-established state of cancer arts, a skilled practitioner would not conclude all cancers could be treated, managed or improved with the same therapeutic agent.
The amount of direction or guidance presented – the instant specification briefly provides an explanation of the biological activity of PRMT5 on page 1 and discusses the implication of PRMT5 inhibitors in the treatment of MTAP-deleted cancers. There is no direction or guidance provided that supports a use of a PRMT5 inhibitor as a drug for treating all cancer.
The amount of guidance or direction to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. MPEP § 2164.03 (quoting In re Fisher, 427 F.2d 833, 839, 166 USPQ 18 24 (CCPA 1970)). As identified supra, the pharmaceutical art is recognized as unpredictable.
Thus, in order to support a claim for treating all cancer a vast amount of evidence is required because such a claim is not supported by the prior art or the instant specification.
The presence or absence of working examples - there are no working or prophetic examples in the specification that demonstrate that the instant compounds or compositions thereof may treat all cancer. The assays in the specification demonstrate that the instant compounds were tested for their ability against lung cancer and pancreatic cancer cell lines (Examples 1-8).
The breadth of the claims – is incommensurate in scope with the disclosure because a fair reading of the specification fails to support a finding that the PRMT5 inhibitor of claim 1 in combination with a taxane could treat all cancer
The quantity of experimentation necessary – generally speaking, the amount of experimentation to transform a molecule into medicine is vast and the success thereof is low. Recent statistics indicate that the attrition rates during drug development remain high. Schafer et al. Drug Discovery Today 2008, 13 (21/22), 913-916. The article makes clear that there are many steps necessary to promote a new molecular entity toward its clinical use, any one of which is cumbersome.
For instance, Schafer et al. discloses: "proof of concept trials have failed when the decision to enter clinical development was based on preclinical experiments using the wrong compound, the wrong experimental model, or the wrong endpoint.” It can be gleaned from this article that a plethora of experimentation is needed to identify the lead compound (i.e. one among many in a Markush-type claim), to establish which preclinical tests are predictive of clinical success, and to establish which diseases are the best to target for each lead compound.
There is generally a vast amount of experimentation to take a drug from bench to the clinic. See e.g., Horig et al. Journal of Translational Medicine 2004, 2(44) (“Successful drug development requires satisfying a matrix of domains from relevance to the disease and the drug-ability of the target through feasibility and convenience of drug delivery, demonstration of favorable benefit-risk profile in order to achieve a drug label that reflects physician and patent acceptance.") The Examiner finds that one of ordinary skill in the art would agree with the statements in these articles; that is, the amount of experimentation required to enable a pharmaceutical drug is extensive.
The level of skill in the art - the level of ordinary skill in the art may be found by inquiring into: (1) the type of problems encountered in the art; (2) prior art solutions to those problems; (3) the rapidity with which innovations are made; (4) the sophistication of the technology; and (5) 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 those 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 typical education level of the active workers in the field of pharmaceuticals and/or medicine, as well as the high degree of sophistication required to solve problems encountered in the art, the Examiner finds that a person of ordinary skill in the art would have at least a college degree in a field related to medicine and/or the pharmaceutical art and at least four years of work experience, i.e. a masters or doctorate level scientist/clinician.
Therefore, claims 1, 4-6, 16, 19, 21-25, and 27-32 are rejected because the Examiner finds that the Wands factors suggest a conclusion that the skilled artisan would not be able to make and use the instant invention without undue experimentation, although the level of skill for an ordinary person in the art is high. That is, due to the breadth of the claims, the unpredictability of the art, the lack of guidance or direction from the disclosure, the lack of any working examples, and the amount of experimentation needed illustrate that a person having ordinary skill in the art would not be able to treat all cancer
Claim Rejections - 35 USC § 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.
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, 19, and 25 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.
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 6 recites the broad recitation of several cancers, and then the claim also uses parenthetical language to provide examples of said cancers, 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.
The term “about” in claims 19 and 25 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6, 16, 19, 21-25, and 27-32 are rejected under 35 U.S.C. 103 as being unpatentable over Mavrakis et al. (WO2016038550A1; cited by applicant on 1449 IDS) in view of Bobinski et al. (WO2021050915A1; cited by Applicant on 1449 IDS) and Kalev et al. (Cancer Cell. 2021;39(2):209-224).
Regarding claims 1-3 and 32, Mavrakis teaches a method for inhibiting the proliferation of MTAP-deficient (claim 1) and CDKN2A-deficient (claim 2) cancer cells (claim 3) comprising administering a therapeutically effective amount of a PRMT5 inhibitor (claim 1) and an additional therapeutic agent (claim 10). Mavrakis teaches this additional therapeutic agent can be docetaxel and paclitaxel (paragraph [00343]), two taxanes.
Mavrakis does not teach the instant PRMT5 inhibitor of claim 1 (pictured below), referred to herein as MRTX1719.
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Bobinski teaches PRMT5 inhibitors for the treatment of cancer (claim 92), and discloses Compound 4-230 or MRTX1719 (Table 3 and claim 89) as a preferred embodiment.
In KSR International Vo. V. Teleflex Inc., 82 USPQ2d (U.S. 2007), the Supreme Court particularly emphasized “the need for caution in granting a patent based on a combination of elements found in the prior art,” (Id. At 1395) and discussed circumstances in which a patent might be determined to be obvious.
In this case at least prong B of KSR applies – substitution of one known element for another. Mavrakis teaches the combination of a PRMT5 inhibitor and an additional therapeutic for the treatment of MTAP-deficient cancer cells. Substitution of the PRMT5 inhibitor for MRXT1719, taught by Bobinski, would be prima facie obvious as the skilled artisan would expect the inhibitors to behave similarly as they share utility. Bobinski teaches a large genus of compounds and preferred embodiments, however the skilled artisan would be guided to choosing MRTX1719, as this compound demonstrates one of the highest antiproliferative effects against the HCT116 MTAP knockout cell line (Table 11; page 316).
As Mavrakis presents a long list of possible additional therapeutic agents the skilled artisan would not be quickly guided to the taxanes from the work of Mavrakis alone
Kalev teaches the combination therapy of a MAT2A inhibitor with docetaxel and paclitaxel. MAT2A, like PRMT5, is part of the methionine metabolic pathway. Inhibition of MAT2A inhibits PRMT5. As PRMT5 inhibition is a downstream effect of MAT2A inhibition, the skilled artisan would be motivated to substitute the MAT2A inhibitor of Kalev with a PRMT5 inhibitor. The work of Kalev then guides the artisan to choosing docetaxel and paclitaxel as the additional therapeutic agents to be combined with the PRMT5 inhibitor.
Thus, all of the elements of claims were known to one of ordinary skill in the art at the time the invention was made and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art at the time of invention. Therefore, the claimed invention, as a whole, would have been obvious to one of ordinary skill in that art at the time the invention was made.
Regarding claims 4-6, Mavrakis teaches the method of treating cancer wherein the cancer is pancreatic cancer, bladder cancer, lung squamous, lung adenocarcinoma, diffuse large B-cell lymphoma (DLBCL), head and neck cancer, liver cancer or breast cancer (claim 15).
Regarding claim 16, Bobinski teaches MRTX1719 (claim 89) (pictured below)
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Regarding claim 19, Bobinski teaches the effective amount of the PRMT5 inhibitor is 0.01 to 300 mg/kg per day (claim 93).
Regarding claims 21 and 27, adjustment of the dosage to reach a therapeutically effective amount would be considered routine optimization in the absence of criticality. See MPEP 2144.05.II.A.
Regarding claims 22-24, Mavrakis and Kalev teach docetaxel and paclitaxel.
Regarding claim 25, Kalev teaches a dose of 5 mg/kg for docetaxel and 15 mg/kg for paclitaxel (SI; Figure S8), but in the absence of criticality adjustment would be considered routine optimization. For docetaxel the standard dosing is dependent on the type of cancer, however it ranges from 60 mg/m2 to 100 mg/m2 (as evidenced by Docetaxel Highlights of Prescribing Information) Paclitaxel also depends on the type of cancer and a range of 100 mg/m2 – 260 mg/m2 is seen (as evidenced by Paclitaxel Highlights of Prescribing Information)
Regarding claims 28-29, Mavrakis teaches the combination may be administered simultaneously, concurrently, or sequentially (paragraph [00135]).
Regarding claims 30-31, Mavrakis teaches the method of treating cancer with a PRMT5 inhibitor can be used for a patient that has had previous chemotherapy (paragraph [00394]).
Conclusion
Claims 1-6, 16, 19, 21-25, and 27-32 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jerica K Wilson whose telephone number is (703)756-4690. The examiner can normally be reached Monday-Friday 9:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571)270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.K.W./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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