DETAILED ACTION
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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 6/2/26 has been entered.
Applicant’s election without traverse of group I, as well as the species reducing the level of Aurora kinase, PROTAC, adult onset PKO or ADPKD, and PKD1 in the reply filed on 6/3/25 is acknowledged.
Drawings
The drawings filed on 4/26/22 and 12/11/25 and 6/2/26 are objected to because they are not fully legible. The figures are very fuzzy and the text cannot be clearly ascertained. The letters, numbers, and symbols on the drawings filed on 6/2/26 are not fully legible.
37 C.F.R. 1.84 states “Character of lines, numbers, and letters. All drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.”
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim 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, 19, 22, 24, 35, 38, 47, and 49-51 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.
The claims are directed to a method of treating Polycystic Kidney Disease (PKD) via administering any PROTAC that reduces the level of Aurora kinase A by mediating its degradation, wherein the PROTAC comprises any first moiety that binds to an E3 ubiquitin ligase and any second moiety that binds to Aurora kinase A.
However, the specification does not adequately describe the structure required for the PROTAC to achieve the recited function. The minimal species of first and second moieties of the specification that bind to E3 ubiquitin ligase or bind to Aurora kinase A are not representative of the entire claimed genus. The specification does not disclose any specific moiety for binding to E3 ubiquitin ligase and discloses that the moiety that binds to Aurora kinase A can be any peptide, small molecule or antibody that binds to Aurora kinase A. Without further description of the structure required for the function, one would not be able to readily envision which moieties bind to E3 ubiquitin ligase or bind to Aurora kinase A and function as claimed; or which peptides, small molecules or antibodies bind to Aurora kinase A and function as claimed.
The specification discloses: In certain embodiments, the compound for reducing levels of Aurora kinase is a PROTAC. A PROTAC is a chimeric construct which is useful for facilitating intracellular degradation of a target protein. To facilitate a protein for degradation by the proteasome (e.g. Degradation of Aurora kinase), the PROTAC is comprised of a first moiety that binds to an E3 ubiquitin ligase and a second moiety that binds to Aurora kinase. These moieties are typically connected with a linker. The PROTAC brings the E3 ubiquitin ligase in proximity with the protein so that it is ubiquitinated and marked for degradation. The moiety of a PROTAC for binding to Aurora kinase can be any peptide, small molecule or antibody that binds to Aurora kinase (page 28).
The specification does not adequately describe the structure required for the PROTAC to reduce the level of Aurora kinase A. The specification does not adequately describe the structure required for the first moiety that binds to an E3 ubiquitin ligase and the second moiety that binds to Aurora kinase. The specification discloses that the moiety of a PROTAC for binding to Aurora kinase can be any peptide, small molecule or antibody that binds to Aurora kinase.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The claims are rejected under the written description requirement for failing to disclose adequate species to represent the claimed genus, the genus being PROTACs comprising first and second moieties that function as claimed.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
Therefore, the scope of the claimed invention is broad and the skilled artisan would not be able to envisage the entire genus claimed of agents that mediate the degradation of any Aurora kinase A such that the skilled artisan would recognize that the applicant was in possession of the claimed genus at the time of filing.
Response to Arguments
Applicant argues that the specification provides a clear description of the PROTAC concept and architecture in the context of Aurora kinase, explaining that (to facilitate proteasomal degradation) a PROTAC includes an E3 ubiquitin ligase-binding moiety and an Aurora kinase-binding moiety (typically connected by a linker) that brings the E3 ligase into proximity with the target to drive ubiquitination and degradation (see for instance page 28 lines 11-25 of the specification as filed).
However, the species of the specification are not representative of the entire claimed genus of any PROTAC that reduces the level of AURKA via mediating its degradation that comprises any moiety that binds to E3 and any moiety that binds to Aurora kinase A. The genus of moieties cannot be clearly ascertained without further description of the structure required for the function.
Applicant argues that the claims are not directed to a new molecule, but rather a new method of use. However, as instantly drafted, the structure required for the claimed molecules of the claimed method has not been adequately described and is not claimed. Applicant argues that the specification discloses alisertib and MK-5108 for species of the second moiety, however these are not representative of the entire claimed genus.
The specification discloses that to facilitate a protein for degradation by the proteasome (e.g. Degradation of Aurora kinase), the PROTAC is comprised of a first moiety that binds to an E3 ubiquitin ligase and a second moiety that binds to Aurora kinase. However, the structure required for each of the moieties to function as claimed has not been adequately described in the specification. The genus of PROTACs comprise an enormous genus of possible structures within them that have not been adequately described.
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) 1,19, 22, 24, 35, 38, 47, and 49-51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Harling et al. (KR20190039567A, published 04/12/2019), in view of Plotnikova et al. (US 2010/0137409 A1), Milutinovic et al. (Quarterly Journal of Medicine, New Series LIII, No. 212, pp. 511-522, 1984), Berndt et al. (Current Opinion in Chemical Biology 2017, 39:126–132), and An et al. (EBioMedicine, 36, (2018), 553–562).
Harling et al. teach: It is desirable to identify inhibitors of kinase activity as potential therapies of disorders associated with aberrant kinase activity.
Harling et al. teach: The selective degradation of target proteins using small molecules is a new approach to the treatment of various diseases. Proteolysis Targeting Chimeric molecules (Protacs) are Afunctional molecules which can simultaneously bind a target protein and an E3 ubiquitin ligase thereby bringing the ligase and target in close proximity These bifunctional molecules allow the efficient ubiquitin transfer from the ligase complex to the target protein which is subsequently recognized by the proteasome and degraded. This degradation of the target protein provides treatment of diseases or conditions modulated through the target protein by effectively lowering the level of said target protein in the cells of the patient. An advantage of Protacs is that a broad range of pharmacological activities is possible, consistent with the degradation/inhibition of targeted proteins from virtually any class or family.
Harling et al. teach: In one aspect of the present invention there is provided a method of treating disorders associated with aberrant kinase activity, wherein the kinase is Adaptor-associated protein kinase 1 (AAK1), Abelson murine leukemia viral oncogene homolog 1 (ABL1), Aurora kinase A
Harling et al. teach: (AURKA), Aurora kinase B (AURKB), Bruton's tyrosine kinase (BTK), Cyclin G-associated kinase (GAK), Interleukin-1 receptor-associated kinase 3 (IRAK3), Large tumor suppressor 1 kinase (LATSl), Mitogen-activated protein kinase 9 (MAPK9), Protein kinase AMP-activated alpha-1 (PRKAAl), Focal adhesion kinase (PTK2), Protein tyrosine kinase 2 beta (PTK2B), Ribosomal protein S6 kinase alpha-1 (RPS6KA1), Ribosomal protein S6 kinase alpha-3 (RPS6KA3), Tyrosine-protein kinase Tec (TEC), said method comprising degrading said kinase.
Harling et al. teach: In a further aspect of the present invention there is provided a Protac compound or pharmaceutically acceptable salt thereof comprising moieties which binds to E3 ubiquitin ligase cereblon and a moiety which binds to Aurora kinase A (AURKA) (Formula I) (instant claims 1 and 49).
Harling et al. recite: 1. A method of treating a disorder associated with abnormal kinase activity, wherein the kinase is selected from the group consisting of an adapter-binding protein kinase 1 (AAK1), aurora kinase A (AURKA), aurora kinase B (AURKB), bruton tyrosine kinase Receptor kinase 3 (IRAK3), protein tyrosine kinase 2 beta (PTK2B), tyrosine-protein kinase Tec (TEC), serine / threonine-protein kinase Wee1 (WEE1), cyclin G-binding kinase (GAK) 1 kinase (LATSl), focal adhesion kinase (PTK2), ribosomal protein S6 kinase alpha-1 (RPS6KA1), and said method comprising degrading said kinase.
Instant claims 19 and 22 recite outcomes of the methods rather than method steps and would therefore necessarily flow from the instant method steps.
Harling et al. does not teach treating Polycystic kidney disease (PKD).
However, it would have been obvious to treat PKD with the PROTAC of Harling et al. because Plotnikova et al. teach that targeting Aurora kinase A inhibits PKD.
Plotnikova et al. teach: [0012] In yet another embodiment of the invention, a method for inhibiting progression of polycystic kidney disease in a patient in need thereof is provided. In one aspect the method entails administration of an effective amount of an aurora kinase inhibitor the patient in an amount effective to inhibit cyst formation in the kidney. The inhibitor may inhibit aurora kinase A or aurora kinase B or it may inhibit both.
One would expect for the PROTAC of Harling et al. to degrade Aurora kinase A and treat PKD (instant claim 1).
Plotnikova et al. teach: [0070] PKD is one of the best-described cilia-related diseases, with mutation of the cilia-localized polycystin proteins 1 and 2 (PKD1 and PKD2) responsible for the significant majority of PKD patients. Therefore, it would have been obvious to screen for mutations of these genes for diagnosis of the condition (instant claim 47).
Plotnikova et al. teach: [0070] One of the surprising results of a recent large study to analyze the cancer genome was the identification of the PKHD1 protein, a ciliary protein which is mutant in autosomal recessive PKD, as commonly mutated in colorectal cancer. Overall, deregulated AurA/HEF1/HDAC6 signaling appears to have broad implications for studies of human development and disease. Therefore, it would have been obvious to screen for mutations in the PKHD1 gene for diagnosis of autosomal recessive PKD (instant claim 38).
Plotnikova et al. teach: [0070] PKD is one of the best-described cilia-related diseases (Wilson, 2001), with mutation of the cilia-localized polycystin proteins 1 and 2 (PKD1 and PKD2) responsible for the significant majority of PKD patients. p130Cas interacts directly with complexes containing PKD1 and PKD2, and also with nephrocystins, cilia-associated proteins that are mutated in a second renal cystic syndrome, nephronophthisis (Benzing et al., 2001).
Plotnikova et al. teach: [0073] In the past two years, increasing attention has focused on the identification of other structural and signaling proteins associated with the cilium, the basal body, or the adjacent plasma membrane. Importantly, many proteins that have been identified as the genetic cause of human developmental defects associated with polycystic kidney disease, including polycystins 1 and 2 (encoded by PKD1, PKD2), fibrocystin (PKHD1), nephrocystins (NPHP1,3-5), and inversin (NPHP2), in each case localize to cilia. Therefore, it would have been obvious to screen for mutations in the NPHP1 and 3-5 genes for diagnosis of NPHP (instant claim 38).
Plotnikova et al. teach: [0138] Finally, ADPKD affects as many as 1 in 500 individuals, and currently has few viable treatment options. We show that low concentrations of drugs that inhibit AurA activity augment PC2-dependent Ca.sup.2+ release, suggesting potential clinical applications in renal proliferation-associated pathologies. Therefore, it would have been obvious for the PKD to be ADPKD (instant claims 35 and 51).
Additionally, it would have been obvious to determine if the subject has the condition before treating them because the goal is to treat an individual that does in fact have the condition (instant claim 35).
It would have been obvious for the age to be in the instantly recited ranges because Milutinovic et al. teach that frequency of specific clinical manifestations was similar in women and men with PKD. End-stage renal failure was present in 5 per cent of the 81 patients younger than age of 40, in 33 per cent of the 27 patients 40-49 years old, and in 47 per cent of the 32 patients aged 50 years or more (summary, page 511). Milutinovic et al. teach that the ages of these patients ranged from 15 to 65 years; 72 per cent of the 30 patients less than 25 years of age, and 22 per cent of the 32 patients older than 50 years were newly diagnosed (page 513). Therefore, patients with PKD were known to be within the instant age ranges (instant claim 24).
It would have been obvious for the moiety targeting Aurora kinase A to be alisertib because Berndt et al. teach that alisertib targets Aurora kinase A and is being evaluated in clinical trials (page 127) and An et al. teach that small molecule drug PROTAC technology has the potential to greatly promote the development of targeted therapy drugs (abstract). An et al. teach that small-molecule PROTACs have many benefits including inducing a rapid, profound and sustained degradation, inducing a robust inhibition of downstream signals, displaying enhanced target selectivity, and overcoming resistance to small molecule inhibitors (abstract). One would reasonably expect these benefits when incorporating alisertib as the Aurora kinase A targeted moiety of the PROTAC of Harling et al. (instant claim 50).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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