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 .
Applicant’s election without traverse of group II and ORY-1001 (iadademstat) in the reply filed on 5/1/26 is acknowledged.
Claims 17-29 and 31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/1/26.
Improper Markush Rejection
Claim 32 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. 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: The claim recites the Markush group “a siRNA chosen from SEQ ID NO:12-15 or a natural or synthetic chemical drug such as IMG-7289 (Bomedemstat), tranylcypromine (TCP), SP-2577 (seclidemstat), INCB059872, CC-90011, GSK2879552, ORY- 1001 (iadademstat), TAK-418, ORY-2001 (Vadifemstat), arborinine, higenamine, kavalacotone, raloxifene, or fenoldopam”.
The siRNA and the small molecule inhibitors have a different structure and act via different mechanisms. The siRNA binds to Argonaute proteins and function to guide those proteins to targets. Accordingly, siRNAs and small molecule inhibitors do not have sufficiently similar structures to provide the same function because each has a structure that dictates that it acts via a different mechanism. With regards to each of the small molecule inhibitors, each have a different chemical structure and mechanism of inhibition. One cannot be substituted for another with expectation of identical activity.
Therefore, the members of the Markush group lack any common substantial structural feature that provides a common use, and the group of alternatives is an improper Markush group. 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 CFR 41.31(a)(1).
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 30 and 32 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.
The claims recite “such as” which is indefinite because it is not clear whether the species are required or if they impart any meaningful limitation. For purposes of the instant examination, the language is interpreted as “selected from the group consisting of”.
It is noted that claim 30 recites a method of treating “patients” (multiple) suffering from “metabolic disorders” (multiple) rather than a method of treating a patient suffering from a metabolic disorder. As instantly drafted, the method can be interpreted as requiring treatment of multiple patients simultaneously wherein the patients each have multiple disorders or wherein each patient has a different disorder. It is believed that applicant intends for the claim to read “A method of treating a patient suffering from a metabolic disorder”. Clarification or correction is required.
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 30 and 32 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 for treating patients suffering from “metabolic disorders associated with altered insulin or glucagon secretion”, such as diabetes mellitus, said method comprising the step of administering to said patients “an inhibitor of KDM1A expression or activity”.
The specification does not adequately describe the genus of metabolic disorders that have any possible association with altered insulin or glucagon secretion. Without further description of the genus, one would not be able to readily recognize which disorders necessarily have any possible association with any alteration of insulin or glucagon secretion. The species of the specification are not representative of the entire claimed genus.
Additionally, the specification does not adequately describe the structure required for an agent to function by inhibiting KDM1A expression or activity. The species of the specification are not representative of the entire claimed genus. The claims are not limited to any specific type of agent that has any specific structural relationship to any specific KDM1A sequence. The claims encompass agents that are specific for another target that have the secondary effect of inhibiting the expression or activity of KDM1A, a genus that has not been adequately described in the specification.
It is noted that the claims do not recite a specific KDM1A nucleotide sequence by SEQ ID NO, but rather refer to the broad genus of KDM1A sequences.
The claims encompass a method of introducing any type of KDM1A inhibitor to inhibit the expression of any KDM1A sequence, as well as encompass any KDM1A homolog or allele from any species known or yet to be discovered of KDM1A, as well as DNA genomic fragments, spliced variants or fragment that retains KDM1A -like activity.
Although the specification discloses some inhibitory molecules as recited in instant claim 32, that are specific for a single KDM1A sequence, the specification does not describe an adequate species to demonstrate that applicant was in possession of the claimed agents within the instant method at the time the invention was made. The instant genus of inhibitory molecules is very large, including aptamers, triplexes, peptides, and miRNAs, for example, that do not have any specific structural relationship with any specific target sequence.
Furthermore, although the specification discloses some inhibitory agents that are specific for a single KDM1A sequence, the specification does not describe such agents directed to any other species of KDM1A to describe the instantly claimed genus of any KDM1A. One of ordinary skill in the art could not make such agents to any KDM1A without knowledge of the sequence and knowledge of the structure of the inhibitory agent.
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 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.
For example, Li et al. (Int. J. Mol. Sci. 2020, 21, 5262, 1-18) teach that an understanding of molecular interactions between small molecules and their targets is critical for drug discovery. It is exemplified that structural biology provides a clear view of the binding modes of protease inhibitors and phosphatase inhibitors. We also demonstrate that structural biology provides insights into the function of a target and identifies a druggable site for rational drug design (abstract). Given the lack of description in the specification, one would not be able to readily recognize which agents or which small molecules (a single species of inhibitors) would in fact have the structure to achieve the recited function.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for agents within the instant enormous genus that are inhibitory of the target as claimed or for metabolic disorders with any association with altered insulin or glucagon secretion. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Claims 30 and 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 a method of inhibiting KDM1A and increasing GIPR via direct delivery of specific inhibitors of a specific KDM1A, does not reasonably provide enablement for a method of treating patients suffering from metabolic disorders with any association to altered insulin or glucagon secretion, such as diabetes mellitus, said method comprising the step of administering to said patients any inhibitor of KDM1A expression or activity. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The claims are directed to a method for treating patients suffering from “metabolic disorders associated with altered insulin or glucagon secretion”, such as diabetes mellitus, said method comprising the step of administering to said patients “an inhibitor of KDM1A expression or activity”.
The specification does not adequately draw a nexus between broad systemic delivery of any possible inhibitor of KDM1A expression or activity and the predictable outcome of the treatment of patients suffering from metabolic disorders with any association to altered insulin or glucagon secretion.
The specification demonstrates that adrenal samples from patients who had undergone adrenalectomy for GIP-dependent Cushing’s syndrome were analyzed for DNA variation and whole exome sequencing. The specification demonstrates inhibition of a specific KDM1A sequence with GSK-LSD1 or siRNAs that are fully complementary to a specific KDM1A sequence (pages 36-37) in vitro with resultant increase in the expression of GIPR (page 49), which is not commensurate in scope with a method of treating patients suffering from “metabolic disorders associated with altered insulin or glucagon secretion”, such as diabetes mellitus, said method comprising the step of administering to said patients “an inhibitor of KDM1A expression or activity”.
The specification does not draw an adequate nexus between delivery of any possible inhibitor of KDM1A targeted to any target that has the effect of any level of KDM1A inhibition and the predictable outcome of treating any possible metabolic disorders associated with altered insulin or glucagon secretion, which encompasses an enormous genus of diseases that have not been shown to be reliant upon KDM1A expression alone.
The specification does not draw an adequate nexus between any level of inhibition of KDM1A and the predictable outcome of treating the instant genus of disorders.
Additionally, there is no guidance in the specification as filed that teaches how to deliver the instantly recited genus of inhibitors, each having different delivery challenges, and predictably treat the instant genus of disorders in vivo.
With regards to siRNAs, a single species of the instant inhibitors, the instant siRNAs are not required to have any specific structural relationship with any specific target sequence. The siRNAs of the specification that resulted in KDM1A inhibition in vitro are targeted to specific regions of a specific KDM1A target sequence. However, the instant claims not only encompass targeting any target that has the secondary effect of inhibiting KDM1A, but also encompasses siRNAs targeted to any possible region of any KDM1A sequence. It is known in the siRNA field that not any siRNA to any target sequence will result in inhibitory effect. Even from those that are inhibitory to KDM1A, not all of this pool would predictably result in treatment effects in vivo.
Although applicant has demonstrated RNA interference in vitro via specific siRNAs that are targeted to specific regions of a specific KDM1A target sequence, applicant is not enabled for mediating RNA interference in vivo by the broadly recited methods, as delivery and effective action therein is known in the art to be unpredictable with regards to dsRNA duplexes. Activity in vitro is not predictable of the in vivo therapeutic effect in the in vivo complex environment.
For example, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888).
Fujita et al. (Int. J. Mol. Sci. 2015, 16, 5254-5270) teach that two types of small RNA molecules, small interfering RNAs (siRNAs) and microRNAs (miRNAs), have a central function in RNAi technology. The success of RNAi-based therapeutic delivery may be dependent upon uncovering a delivery route, sophisticated delivery carriers, and nucleic acid modifications (page 5254). Fujita et al. teach that the success of an RNAi-based therapy in clinical trials rests on careful selection of target genes and miRNAs. Moreover, we suggest that a delivery route, sophisticated delivery carriers, chemical modification, and modified RNAi platforms are needed to enhance RNAi effects in cancer cells (pages 5262-5263).
As outlined above, it is well known that there is a high level of unpredictability in the RNAi art (a single species of the instant inhibitors that is not elected) for therapeutic in vivo applications and design. The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of treating a broad and undefined genus of disorders via broad systemic delivery of a broad genus of agents that act via different mechanisms and have different levels of activity encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of any KDM1A inhibitor of the instant genus in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful treatment of any possible disorder of the instantly recited genus. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the molecule in vivo, delivery of the molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
With regards to treating any metabolic disorder with any association to altered insulin:
Claim(s) 30 and 32 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Maes et al. (Cancer Cell 33, 495–511, March 12, 2018), ad evidenced by Ye et al. (Blood (2018) 132 (Supplement 1): 908).
Maes et al. teaches ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the treatment of Acute Leukemia (title) (instant claims 30 and 32).
Maes et al. teach: The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors (Summary, page 495).
Maes et al. teach: To determine the in vivo efficacy of ORY-1001 against ALL, we used a human T-ALL model. Treatment of the ALL-T1-bearing xenograft mice with ORY-1001 (0.0125 mg/kg, intraperitoneally [i.p.]) was well tolerated (Figure 7F). ORY-1001 lowered the percentage of circulating human leukemic blasts analyzed at day 19 after tumor cell inoculation and significantly prolonged survival (26%, p < 0.0001) of these patient-derived xenograft mice (Figures 7G and 7H) (page 506).
Although Maes et al. does not teach that leukemia is a metabolic disorder associated with altered insulin, it is a metabolic disorder associated with altered insulin as evidenced by Ye et al.
Ye et al. teaches: We demonstrate that through induction of insulin resistance, leukemic disease alters systemic metabolism and thereby redirects systemic glucose to be preferentially available to malignant cells (abstract).
Therefore, Maes et al. teach a method of treating a patient suffering from a metabolic disorder associated with altered insulin, leukemia, comprising administering ORY-1001.
Therefore, the claims are anticipated by Maes et al.
With regards to diabetes mellitus:
Claim(s) 30 and 32 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Gauthier et al. (WO 2020/152280 A1).
Gauthier et al. teach: The present invention is focused on the use of lysine specific demethylase (LSD1) inhibitors for the treatment of type 2 diabetes, by means of the re-differentiation of pancreatic beta cells once they have been de-differentiated (abstract).
Gauthier et al. teach: Diabetes mellitus type 2 (also known as type 2 diabetes) is a long-term metabolic disorder that is characterized by high blood sugar, insulin resistance, and relative lack of insulin (page 1).
Gauthier et al. teach: It is important to note that, in a preferred embodiment, the inhibitors used in the present invention are not only directed to the inhibition of the activity of LSD 1 but they are also directed to inhibit the expression of KDM1A gene which encodes the protein LSD1. This means that, according to a preferred embodiment of the invention, the re-differentiation of pancreatic b-cells and the treatment of type 2 diabetes can be achieved not only by inhibiting the activity of LSD 1 but also by inhibiting the expression of KDM1A gene (page 3) (instant claim 30).
Gauthier et al. teach: In a preferred embodiment, the LSD1 inhibitor is the compound Trans-Nl-((lR,2S)-2- phenylcyclopropyl)cyclohexane- 1,4-diamine (ORY-1001) (CAS Number: 1431304-21-0), characterized by Formula II. Moreover, as explained above, the most important technical feature of the present invention is the inhibition of LSD1 and /or KDM1A for treating type 2 diabetes, irrespective of the molecule or compound which is used for reaching said inhibition. In this regard, although compounds of Formula I, preferably the compound of Formula II, is especially preferred in the present invention, any of compound or molecule able to inhibit LSD1 and /or KDM1A could be used according to the present invention for treating type 2 diabetes (page 5) (instant claim 32).
Therefore, the claims are anticipated by Gauthier et al.
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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