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 .
Claim of Foreign Priority
Applicant’s claim of foreign priority and foreign priority documents are acknowledged by the Office.
Election/Restrictions
Applicant’s election without traverse of Group II, corresponding to claims 15, 17, 23, and 24, in the reply filed on July 27, 2026, is acknowledged. Applicant further elected compound 1 as the elected species. Applicant indicates that all claims are amended and are now encompassing of the elected species.
Status of the Claims
Claims 2-5, 8, 13-15, 17, 21, 23, and 24 are pending and examined.
Claim Objections
Claim 4 recites “increases producing” and it appears to intend to recite “increases production.” Correction is requested.
Claim 13 recites “brining” rather than bringing. Correction is requested.
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 2-5, 8, 13-15, 17, 21, 23, and 24 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 treating certain cancers in which an aberrant splicing regulation is present, comprising administering compound 1 or compound 2 of the instant Specification, is not considered enabled for administering all of the other compound species encompassed by Formulae (I)-(VII), for improving tumorigenicity in all forms of tumors (including tumors of the CNS) by “modulating” activity of SRSFs. 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 standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below
Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
In the instant case, the claimed invention pertains to a method of “improving tumor immunogenicity” comprising administering a compound that modulates serine/arginine rich splicing factors when brought into contact with a tumor.
The State of the Prior Art and the Relative Skill of those in the Art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.”
The examiner cites: J. Tazi et al. (Biochimica et Biophysica Acta 2009). Tazi teaches aberrant splicing regulation leads to significantly altered activity following mutations, i.e., “[d]ue to the complexity of the splicing regulation, the effects of mutations are difficult to predict…,” [emphasis added], please see lines 1-5 in column 1 on page 17. Further, “The example of FD illustrates the complexity of mutations in splice sites that have to be carefully analyzed within the context of other regulatory elements.” See p17, 1st full par.
Thus, splicing regulation is recognized as an extremely complex and does not appear to be recognized as extrapolatable to treat all forms of cancers or to have specific effects without being tested.
As discussed above, the instantly claimed invention pertains to a method treating all tumors caused by aberrant splicing regulation comprising administering undefined compounds (claim 15). At the time the instant application was filed, it would have been known by those of ordinary skill in the art that - due in large part to the strict requirement of complementarity between a compound and its corresponding binding site on a target receptor or enzyme - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc.) would interact with the given target to elicit a related biological response.
Accordingly, at the time the invention was made, the relative skill of those in the art tasked with identifying compounds exerting an activity of interest would have been high, as the ordinarily skilled artisan would have had, at minimum, a Ph.D. and experience with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods. Deciding which technique to use would have been determined by the skilled artisan’s knowledge regarding the compound and target of interest. Ligand based drug design relies on knowledge of a compound or compounds of interest (i.e., ligands) to derive new compounds that will, in theory, similarly interact with the target of interest to elicit the activity of interest. Conversely, structure based drug design relies on knowledge of the three dimensional structure of the target of interest (i.e., receptor, ion channel, or enzyme) to derive new compounds that will, in theory, interact with the target of interest to elicit the activity of interest. In either case, the compounds derived from these techniques (applied alone or in combination) are then subjected to in vitro testing for validation.
The Level of Predictability in the Art: Once a compound has been identified by ligand based and/or structure based drug design methods as potentially binding to the target molecule, it must be evaluated. However, as discussed by Anderson (Chemistry and Biology 10:787-797, 2003), “it is important to consider that the ranking assigned by the scoring function is not always indicative of a true binding constant, since the model of the target:ligand interaction is inherently an approximation. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation” (see page 794, column 1). By that point, as noted by Thiel (Nature Biotechnology 2:513-519, 2004), “libraries are small and hit rates are on the order of one in ten” (see page 517, column 2). This low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised. This is certainly true in the case of abnormalities in splicing regulation.
The examiner cites: J. Tazi et al. (Biochimica et Biophysica Acta 2009). Tazi teaches aberrant splicing regulation leads to significantly altered activity following mutations, i.e., “[d]ue to the complexity of the splicing regulation, the effects of mutations are difficult to predict…,” [emphasis added], please see lines 1-5 in column 1 on page 17. Further, “The example of FD illustrates the complexity of mutations in splice sites that have to be carefully analyzed within the context of other regulatory elements.” See p17, 1st full par.
The Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the Specification discloses the preparation of less than approximately 50 compound species encompassed by the claimed formulas. The examples in the instant Specification being at the top of page 36. Examples show how compound 1 (i.e. the elected species) can act as a splicing modulator targeting SRSFs. See par. 73. It was shown to suppress tumor growth in a CD8+Tcell and tumor MHC class I-dependent manner and enhance PD-1 therapy. See par. 73. In total, the Specification appears to test provide some data for compound 1 and compound 2.
In vivo efficacy in MC38 (i.e., colon adenocarcinoma) tumor cells was tested. Compound 1 was tested alone or in combination with an alphaPD-L1 compound. Compound 1 was the only compound described in the Examples on page 36 through page 46. Compound 2 was described at the bottom of page 47.
PNG
media_image1.png
162
186
media_image1.png
Greyscale
.
Compound 2 is the only other compound that is described in the examples as being tested. Thus, the working examples are insubstantial relative to the breadth of all tumors. There is also no data on whether or not a claimed compound can cross the blood brain barrier at therapeutically efficacious concentrations.
Table 1 provides examples of specific peptides to validate “Compound 1 induced immunogenic splice neoantigens). See par.’s 83 and 84. There are no other peptide deletions, substitutions, or additions that were evaluated.
Scope or Breadth of the Claims: As stated in MPEP 2164.01(c), “[w]hen a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation.” Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, the Federal Circuit has repeatedly held that “the specification 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 (Fed. Cir. 1993) (emphasis added).
At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention, In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims," Amgen, Inc, v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation.”
As to the first inquiry, as discussed above, the claims are drawn to a method of treating any form of cancer with any compound that can enhance production of a peptide that increase immunogenicity in any tumor, is capable of modulating Cdc2-like kinase, can increase production of a peptide that has an ability to improve tumor immunogenicity in any type of tumor. As such, the claim is extremely broad with respect to the disclosure. The second inquiry is discussed in detail below.
Amount of Experimentation Necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to a method of administering any splicing-controlling compound that modulates SRSFs, including compounds of Formula (II)-(VIII), which are alleged by the Specification to act as suppressors of abnormal splicing. Further, such method includes treating all tumors. Even further, such methods include producing a splice neoantigen comprising a peptide that can have additions, deletions, or substitutions. Testing these compounds for specific activity in Cdc2-line kinase modulation, improving immunogenicity, in all tumors with a vast breadth of agents would require undue experimentation. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of the scope of compounds encompassed by the claims. In this case, the Specification provides limited data on compound 1 and compound 2. Page 45 of the Specification refers to a rationale as to why this should work in other cells and a “broad spectrum of cancers,” there does not appear to be any data in the Specification to support this.
Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the hundreds of millions of compounds encompassed by Formulae (II)-(VIII) would exert the alleged activity based on the limited disclosure of less than 50 active compounds wherein only compounds 1 and 2 are tested. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similar activity, the skilled artisan would have also known that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, as evidenced by Tazi et al, the effects of compounds that suppress errors in splicing regulation in particular are difficult to predict since genetic mutations due to errors in splicing regulation are large in number and are extremely unpredictable. Thus, in order to identify usable compounds of Formulae (II)-(VIII), the skilled artisan (at minimum) would have to carry out ligand based drug design methods using the disclosed compounds and peptides of Table 1 as a starting point and, assuming the structure of the target receptor was known, combine the findings with data derived from structure based drug design methods to arrive at a small library of “lead” compounds believed to possess the activity of interest. The skilled artisan would then synthesize lead compounds that are within Formulae (II)-(VIII) for in vitro testing. At this point, however, even "the top scoring molecule could fail in vitro assays” (see Anderson, page 794, column 1) and “hit rates are on the order of one in ten” (see Thiel page 517, column 2). Given the unpredictability of splicing abnormalities in particular, as evidenced by Tazi et al, it is highly unpredictable whether any compound within the genus of compounds of Formulae (II)-(VIII) identified by rational drug design based on the instant disclosure would, in fact, be usable. Whether the other compounds of Formulae (II)-(VIII), (i.e. those not identified by rational drug design based on the instant disclosure) would be usable is even less predictable. As such, the only way to ascertain which of the thousands of claimed compounds encompassed by Formulae (II)-(VIII) are usable to treat all forms of cancers through specific mechanisms described would require undue experimentation. That is, the only way one skilled in the art is enabled to use the entire scope of the claim based on the instant disclosure entails undue experimentation.
To overcome this rejection, Applicant should narrow the genus of the compounds encompassed by the claims, as well as the scope of genetic diseases caused by aberrant splicing regulation to be treated, such that they bear a reasonable correlation with the disclosure.
Claim Rejections - 35 USC § 112 (Written Description)
Claims 2-5, 8, 13-15, 17, 21, 23, and 24 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.
Applicant did not possess the following:
All compounds “capable of modulating” a Cdc2-like kinase (claim 2);
All compounds that can enhance production of any peptide that improves tumor immunogenicity in any tumor (claim 3);
All recited peptides with any combination of deletions, substitutions, and additions that have “the ability” to improve tumor immunogenicity in any tumor (claim 4);
All splice-controlling compounds that modulate SRSFs (claim 15); and
All splice-neoantigens that are produced by a method of claim 15 (claim 21).
The examiner notes that the above are included in all pending claims directly or indirectly.
The MPEP §2163 states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. In the case of chemical entities, Applicant's attention is further directed to Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089, 118 S. Ct. 1548 (1998), which notes that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, “not a mere wish or plan for obtaining the claimed chemical invention.” While the court recognizes that, “[i]n claims involving chemical materials, generic formulae usually indicate with specificity what the generic claims encompass” (Id.), it is also recognized that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim and/or the genus must be sufficiently detailed to show that applicant was in possession of the claimed invention as a whole (see Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555 (Fed. Cir. 1991)). If a genus has substantial variance, the disclosure must present a sufficient number of representative species that encompass the genus in order to adequately describe the genus (i.e., the disclosure must describe a sufficient variety of species to reflect the variation within that genus). See MPEP § 2163. Otherwise, as stated by the court in Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company (Fed. Cir. 2010), “a generic claim may define the boundaries of a vast genus of chemical compounds, and yet the question may still remain whether the specification, including original claim language, demonstrates that the Applicant has invented species sufficient to support a claim to a genus. The problem is especially acute with genus claims that use functional language to define the boundaries of a claimed genus, as in the instant case. In such a case, the functional claim may simply claim a desired result, and may do so without describing species that achieve that result. But the specification must demonstrate that the Applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.”
While the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number of species to adequately describe a broad generic. For example, in In re 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 1008 (Fed. Cir. 1989). In the instant case, it is similarly determined that the disclosure of approximately 50 structurally related compounds does not adequately describe a subgenus embracing hundreds of millions of additional compound species bearing no structural relationship with those approximately 50 disclosed compounds. That is, the Specification does not disclose a sufficient variety of species to reflect the extreme variance in the genus.
Further, many of the claims are defined by any compound that produces a result or any peptide with any change that produces a result.
35. The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”) Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
As such, claims 2-5, 8, 13-15, 17, 21, 23, and 24 are rejected.
Claim Rejections - 35 USC § 102
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.
Claim 8, 13-15, and 17 are rejected under 35 U.S.C. 102(a)(2) as being by Bradley et al., (US2023/0190707).
Bradley teaches contacting a cancer cell with an agent that modulates RNA splicing. These methods are to enhance cancer susceptibility to immunotherapeutic agents. See Abstract. The enhanced combination includes an inhibitor of RNA splicing factors with an immunotherapeutic agent. See par. 8 and 10. In further embodiments, the immunotherapeutic agent is an immune checkpoint inhibitor. See Abstract. Examples of immune checkpoint inhibitors are PD-1, PD-L1, and many others. Such contact can be in vivo by administration to a subject. See par. 12. Examples of serine/arginine RNA splicing factor inhibitors taught and claimed include: SRSF9 and RBM39. See prior art claims 5 and 10. The examiner notes that the official name for SRSF9 is: “serine and arginine-rich splicing factor 9.” The neo-antigens production sensitizes the cancer cells to immunotherapies, “resulting in synergistic effects.” See par. 34. Bradley further notes that these compounds induce splicing derived MHC-I bound antigens that can be combined with anti-DP1 to enhance response to checkpoint blockade. See par. 57.
As such, claims 8, 13-15, and 17 are anticipated by the prior art.
Claim 8 and 15 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being by Bieberich et al., (US2019/0076416).
Bieberich teaches treating cancers by administering a modulator of an RNA splicing factor. Further, these compounds specifically include those compounds that are serine/arginine-rich splicing factors, including but not limited to SRFSb, SRSF5, among others. Table 1 provides further examples of SRSF1, SRSF5, SRSF6, SRSF7, SRSF10 splicing factors that can be inhibited as well as a number of splicing factor inhibitors that target other regions. Additionally, SRPIN340 which is a small molecule inhibitor SRPK1 (a serine/arginine protein kinase 1) was tested. See par. 109. These combinations are also referred to as synergistic.
As such, claims 8 and 15 are anticipated by the prior art.
Claim Rejections - 35 USC § 103
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.
Claims 2-5, 8, 13-15, 17, 21, 23, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Bradley et al., (US2023/0190707), in view of Hagiwara et al., (US2016/0152620).
Bradley teaches contacting a cancer cell with an agent that modulates RNA splicing. These methods are to enhance cancer susceptibility to immunotherapeutic agents. See Abstract. The enhanced combination includes an inhibitor of RNA splicing factors with an immunotherapeutic agent. See par. 8 and 10. In further embodiments, the immunotherapeutic agent is an immune checkpoint inhibitor. See Abstract. Examples of immune checkpoint inhibitors are PD-1, PD-L1, and many others. Such contact can be in vivo by administration to a subject. See par. 12. Examples of RNA splicing factors inhibitors claimed include SRSF9 and RBM39. See prior art claims 5 and 10. The examiner notes that the official name for SRSF9 is: “serine and arginine-rich splicing factor 9.” The neo-antigens production sensitizes the cancer cells to immunotherapies, “resulting in synergistic effects.” See par. 34. Bradley further notes that these compounds induce splicing derived MHC-I bound antigens that can be combined with anti-DP1 to enhance response to checkpoint blockade. See par. 57.
Bradley does not teach a claimed compound.
Hagiwara teaches and claims the claimed compound in paragraphs 10, 193, 196, and others for treating diseases associated with abnormal splicing. See Abstract. This includes cancer. See par.’s 9, 41, 127, 129, and 131, e.g. Also see prior art claims 25 and 27. Also see paragraphs 66 and 67, wherein “Y” is defined to include chlorine. The compound can be used and brought into contact with human cells or subjects. See par. 21. Embodiments include isomers, mixtures, salts, prodrugs, etc. see par. 59 and 60. The Abnormal splicing includes that of the pre-mRNA and the active agents is capable of inhibiting the abnormal splicing. See par. 16. The splicing is taught to contribute to the development or progression of cancer, e.g. See par. 183.
When the claimed compound is administered to a claimed subject with cancer, the results of that method will be a direct result of the active steps undertaken. The claimed compound is taught to be administered to a claimed subject. A “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” See Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003).
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to combine the cited prior art to arrive at the claimed methods. One would be motivated to do so because Bradley teaches using a combination of an RNA splicing modulator compound with an immune checkpoint inhibitor to treat numerous forms of cancers. In some instances these RNA modulators include those that target serine/arginine rich splicing factors. Further, Hagiwara teaches the claimed compounds as those that are capable of inhibiting RNA splicing that can be used to treat cancers. As such, using a splicing factor modulator compound as taught by Hagiwara would be obvious to substitute and include in those methods taught by Bradley. Such substitution of one cancer treating RNA splicing modulator compound for another would have a reasonable and predictable expectation of success. Such success is based on a substitution of equivalent functionalities and their known and established independent utilities in treating cancers.
Claims 2-5, 8, 13-15, 17, 21, 23, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Bradley et al., (US2023/0190707), in view of Bieberich et al., (US2019/0076416), and in further view of Hagiwara et al., (US2016/0152620).
Bradley teaches contacting a cancer cell with an agent that modulates RNA splicing. These methods are to enhance cancer susceptibility to immunotherapeutic agents. See Abstract. The enhanced combination includes an inhibitor of RNA splicing factors with an immunotherapeutic agent. See par. 8 and 10. In further embodiments, the immunotherapeutic agent is an immune checkpoint inhibitor. See Abstract. Examples of immune checkpoint inhibitors are PD-1, PD-L1, and many others. Such contact can be in vivo by administration to a subject. See par. 12. Examples of serine/arginine rich RNA splicing factor inhibitors claimed include SRSF9 and SRRM. See prior art claims 5 and 10. The examiner notes that the official name for SRSF9 is: “serine and arginine-rich splicing factor 9.” The neo-antigens production sensitizes the cancer cells to immunotherapies, “resulting in synergistic effects.” See par. 34. Bradley further notes that these compounds induce splicing derived MHC-I bound antigens that can be combined with anti-DP1 to enhance response to checkpoint blockade. See par. 57.
Similarly, Bieberich teaches treating cancers by administering a modulator of an RNA splicing factor. Further, these compounds specifically include those compounds that are serine/arginine-rich splicing factors, including but not limited to SRFSb, SRSF5, among others. Table 1 provides further examples of SRSF1, SRSF5, SRSF6, SRSF7, SRSF10 splicing factors that can be inhibited as well as a number of splicing factor inhibitors that target other regions. Additionally, SRPIN340 which is a small molecule inhibitor SRPK1 (a serine/arginine protein kinase 1) was tested. See par. 109. These combinations are also referred to as synergistic.
Bradley and Bieberich do not teach a claimed compound.
Hagiwara teaches and claims the claimed compound in paragraphs 10, 193, 196, and others for treating diseases associated with abnormal splicing. See Abstract. This includes cancer. See par.’s 9, 41, 127, 129, and 131, e.g. Also see prior art claims 25 and 27. Also see paragraphs 66 and 67, wherein “Y” is defined to include chlorine. The compound can be used and brought into contact with human cells or subjects. See par. 21. Embodiments include isomers, mixtures, salts, prodrugs, etc. see par. 59 and 60. The Abnormal splicing includes that of the pre-mRNA and the active agents is capable of inhibiting the abnormal splicing. See par. 16. The splicing is taught to contribute to the development or progression of cancer, e.g. See par. 183.
When the claimed compound is administered to a claimed subject with cancer, the results of that method will be a direct result of the active steps undertaken. The claimed compound is taught to be administered to a claimed subject. A “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” See Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003).
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to combine the cited prior art to arrive at the claimed methods. One would be motivated to do so because Bradley teaches using a combination of an RNA splicing modulator compound with an immune checkpoint inhibitor to treat numerous forms of cancers. In some instances these RNA modulators include those that target serine/arginine rich splicing factors. Even further, Bieberich specifically teaches treating cancers with RNA splicing inhibitors of serine/arginine RNA. Hagiwara teaches the claimed compounds as those that are capable of inhibiting RNA splicing that can be used to treat cancers. As such, using a splicing factor modulator compound as taught by Hagiwara would be obvious to substitute and include in those methods taught by Bradley. Such substitution of one cancer treating RNA splicing modulator compound for another would have a reasonable and predictable expectation of success. Such success is based on a substitution of equivalent functionalities known to treat claimed cancers, as well as their known and established independent utilities in treating cancers. Even further, combination therapy with an immunotherapy is similarly motivated.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 2-5, 8, 13-15, 17, 21, 23, and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 9,879,014, in view of Bradley et al., (US2023/0190707).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘014 patent are directed to a pharmaceutical composition comprising the claimed compound. See prior art claim 5. The claims are product claims although their utility is included in the claims to treat cancer cells. See prior art claim 2. As such, the claims are directed to the same agent for treatment of a same cell or subject population. As noted above, Bradley teaches combination therapy with agent that are designed to treat cancer by mitigating abnormal splicing activity as the claims are designed to do. Bradley teaches immunotherapy to work synergistically with an RNA splicing modulator.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JARED BARSKY/Primary Examiner, Art Unit 1628
Prosecution Insights