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 1-14, 20-22, and 28-30 are pending in the instant application.
Claims 1-14, 20-22, and 28-30 are examined herein.
Priority
Acknowledgement is made of the applicant’s claim for foreign priority. It is noted, however, that applicant has not provided an English translation of the certified copy of Chinese Patent No. CN2022104755471, filed on 29 April 2022, as required by 35 U.S.C. 119(b). Therefore, the priority date of the instant application is 19 May 2022, the filing of PCT/EP2022/063661. Without the English translation, one cannot ascertain if the instant invention is present in the Chinese patent. Therefore, art prior to the PCT date may be cited against the claims.
Information Disclosure Statement
The information disclosure statement (IDS), submitted on 14 August 2025, 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 1-3, 5, 8, and 11-12 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 colorectal, pancreatic, hepatic, or ovarian cancer fails to provide the required enablement for treatment of all proliferative diseases. 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 a method of treating a proliferative disorder. The specification fails to provide information that would allow the one skilled in the art to practice treating all proliferative disorders
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 a proliferative disorder comprising administering a compound of Formula (I) and a second pharmaceutical agent selected from (i) a protein kinase inhibitor; (ii) a ribonucleotide reductase inhibitor; and (iii) a proteasome inhibitor.
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 histone deacetylases, which can be used to treat several disease including certain cancers, interstitial fibrosis, autoimmune and inflammatory diseases, and metabolic disorders (Tang et al. Clin Sci (Lond). 2013;124(11):651–662).
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 HDAC on pp. 1, and discusses the implication of HDAC inhibitors in the treatment of certain diseases. There is no direction or guidance provided that supports a use of a HDAC inhibitor as a drug for treating al proliferative diseases.
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 proliferative disease 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 disease. The assays in the specification demonstrate that the instant compounds were tested for their oncolytic efficacy against liver, pancreatic, colorectal, and ovarian cancer cell lines.
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 compounds of instant formula (I) may treat all proliferative diseases in a patient.
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 1-14, 20-22, and 28-30 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 prevent a [insert] disease.
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.
Claim(s) 1-7, 20-22, and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (Clin Cancer Res.2014;20(5):1274–1287) in view of Mora et al. (WO2011039353A1; cited by Applicant on 1449 IDS).
Regarding claim 1, Chen teaches the method of treating hepatic cancer comprising administering a combination of MPT0E028, an HDAC inhibitor, and sorafenib, a protein kinase inhibitor.
Chen does not teach the HDAC inhibitor to be a compound of Formula (I), also known as QTX25.
Mora teaches compounds of Formula (I) (pictured below) as HDAC inhibitors for the treatment of cancer. Mora presents the preferred embodiment of compound 15, which is the instant compound of Formula(I) or QTX125.
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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. Chen teaches the combination of an HDAC inhibitor and a protein kinase inhibitor for the treatment of hepatic cancer. It would be prima facie obvious to one of ordinary skill in the art to substitute the HDAC inhibitor taught by Chen for QTX25 taught by Mora. MPT0E028 and QTX25 belong to the same drug class and would be expected to treat the same condition. Moreover, the skilled artisan would be guided to choosing QTX25 from all the embodiments presented by Mora as it is the most efficacious compound presented and is shown to have a desirable IC50 value against three liver cancer cell lines. Therefore, as Chen and Mora teach the compounds of the same drug class for treatment of the same condition, the skilled artisan would be motivated to substitute one HDAC inhibitor for another.
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 claim 2, both Chen and Mora teach the treatment of cancer.
Regarding claim 3, both Chen and Mora teach the treatment of a solid tumor.
Regarding claim 4, both Chen and Mora teach hepatic tumors.
Regarding claim 5, Chen teaches the kinase inhibitor sorafenib.
Regarding claims 6 and 7, Chen teaches the method of treating hepatic cancer.
Regarding claims 20, 21, and 28, Mora teaches a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable excipient (claim 15). Mora additionally teaches the composition can comprise an additional therapeutic to provide a combination therapy (page 21, line 26). For the reasons stated above it would be prima facie obvious for the additional therapeutic to be the kinase inhibitor, sorafenib.
Regarding claim 22, Chen teaches the administration of 100 mg/kg of MPT0E028 and 60mg/kg of sorafenib. Which equates to 0.000290 mol/kg of MPT0E028 and 0.000129 mol/kg of sorafenib, which falls within the claimed molar ratio range.
Claim(s) 1-4, 11-14, 20-21, and 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Janyst et al. (Oncology Reports.2018;39(4):1999-2005) in view of Mora et al. (WO2011039353A1; cited by Applicant on 1449 IDS).
Regarding claim 1, Janyst teaches the method of treating ovarian cancer comprising administering the HDAC inhibitor, scriptaid, and the proteasome inhibitor, bortezomib.
Janyst does not teach the HDAC inhibitor to be QTX25.
Mora teaches compounds of Formula (I) (pictured below) as HDAC inhibitors for the treatment of cancer. Mora presents the preferred embodiment of compound 15, which is the instant compound QTX125.
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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. Janyst teaches the combination of an HDAC inhibitor and a proteasome inhibitor for the treatment of ovarian cancer. It would be prima facie obvious to one of ordinary skill in the art to substitute the HDAC inhibitor taught by Janyst for QTX25 taught by Mora. Scriptaid and QTX25 belong to the same drug class and would be expected to treat the same condition. Moreover, the skilled artisan would be guided to choosing QTX25 from all the embodiments presented by Mora as it is the most efficacious compound presented and is shown to have a desirable IC50 value against two ovarian cancer cell lines. Therefore, as Janyst and Mora teach the compounds of the same drug class for treatment of the same condition, the skilled artisan would be motivated to substitute one HDAC inhibitor for another.
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 claim 2, both Janyst and Mora teach the method for the treatment of cancer.
Regarding claim 3, both Janyst and Mora teach the method for a solid tumor.
Regarding claim 4, both Janyst and Mora teach ovarian cancer.
Regarding claim 11, Janyst teaches the proteasome inhibitor bortezomib.
Regarding claims 12-14, Janyst teaches the method for the treatment of ovarian cancer.
Regarding claims 20, 21, and 30, Mora teaches a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable excipient (claim 15). Mora additionally teaches the composition can comprise an additional therapeutic to provide a combination therapy (page 21, line 26). For the reasons stated above it would be prima facie obvious for the additional therapeutic to be the proteasome inhibitor, bortezomib.
Claim(s) 1-4, 8-10, 20-21, and 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (Scientific Reports.2017;7:41615) in view of Mora et al. (WO2011039353A1; cited by Applicant on 1449 IDS).
Regarding claim 1, Lee teaches the method of treating pancreatic caner with the HDAC inhibitor, CG200745, and the ribonucleotide reductase inhibitor, gemcitabine.
Lee does not teach the HDAC inhibitor to be QTX25.
Mora teaches compounds of Formula (I) (pictured below) as HDAC inhibitors for the treatment of cancer. Mora presents the preferred embodiment of compound 15, which is the instant compound QTX125.
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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. Lee teaches the combination of an HDAC inhibitor and a ribonucleotide reductase inhibitor for the treatment of pancreatic cancer. It would be prima facie obvious to one of ordinary skill in the art to substitute the HDAC inhibitor taught by Lee for QTX25 taught by Mora. CG200745 and QTX25 belong to the same drug class and would be expected to treat the same condition. Moreover, the skilled artisan would be guided to choosing QTX25 from all the embodiments presented by Mora as it is the most efficacious compound presented and is shown to have a desirable IC50 value against three pancreatic cancer cell lines. Therefore, as Lee and Mora teach the compounds of the same drug class for treatment of the same condition, the skilled artisan would be motivated to substitute one HDAC inhibitor for another.
Regarding claim 2, both Lee and Mora teach the method for the treatment of cancer.
Regarding claim 3, both Lee and Mora teach the method for a solid tumor.
Regarding claim 4, both Lee and Mora teach pancreatic cancer.
Regarding claim 8, Lee teaches the ribonucleotide reductase inhibitor, gemcitabine.
Regarding claims 9-10, Lee teaches the treatment of pancreatic cancer.
Regarding claims 20, 21, and 29, Mora teaches a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable excipient (claim 15). Mora additionally teaches the composition can comprise an additional therapeutic to provide a combination therapy (page 21, line 26). For the reasons stated above it would be prima facie obvious for the additional therapeutic to be the ribonucleotide reductase inhibitor, gemcitabine.
Conclusion
Claims 1-14, 20-22, and 28-30 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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