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 .
Status of the Claims and Response to Restriction Requirement
Claims 1-20 are pending as of the response filed 07/13/2026. Applicant’s election of group II claims without traverse, is acknowledged. Claims 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant’s election of a species of a combination therapeutic comprising SP-2577 (Seclidemstat) in combination with an agent that targets ABL2 pathway, say an ABL2 knockdown agent, siABL2, without traverse is acknowledged. Claim 2 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Claims 1 and 3-15 are examined to the extent to which they are readable on the above identified elected invention and elected species.
Priority
This application is a 371 of PCT/US2022/047319 filed 10/20/2022,
PCT/US2022/047319 has PRO 63/270,005 filed 10/20/2021.
The subject matter of the instant claims are supported by the provisional application, PRO 63/270,005. Accordingly, the effective filing date of instant claims 1 and 3-15 and 29 is 10/20/2021.
Information Disclosure Statement
The information disclosure statement submitted 04/05/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings Objected To
The drawings are objected to because figures 2 and 9A, are illegible and difficult to read.
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 - Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(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 and 3-8 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 a subject having Ewing’s sarcoma, using a pharmaceutical combination of SP-2577 and a ABL2 pathway inhibitor, does not reasonably provide enablement for a method of treating a subject having Ewing’s sarcoma, using a pharmaceutical combination of SP-2577 and any ABL inhibitor being broadly claimed. 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. This is a scope of enablement rejection.
To be enabling, 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, 1561 (Fed. Cir. 1993). The determination that "undue experimentation” would have been needed to practice the claimed invention in full scope is not a single, simple factual determination.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In re Wands, 8 USPQe2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
(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.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons:
The breadth of the claims/The nature of the invention
The claims recite a method of treating a subject having Ewing's sarcoma, the method comprising the step of administering to the subject a therapeutically effective amount of a first pharmaceutical composition comprising SP-2577 and a second pharmaceutical composition comprising an ABL inhibitor. The claim is drawn to a broad category of compounds based on what they do (their function) rather than what they are (their chemical structure). ABL inhibitors can be chemical compounds or allosteric/peptidic/protein-based molecules. The instant specification only provides a handful of examples of an ABL inhibitor in Para. [0008] of the specification. The scope of the claims is very broad.
The state of the prior art/The level of predictability in the art
Zollner et al. (Ewing Sarcoma—Diagnosis, Treatment, Clinical Challenges and Future Perspectives, 14 April 2021, hereinafter Zollner), Greuber et al. (Role of ABL Family Kinases in Cancer: from Leukemia to Solid Tumors, 26 February 2014, hereinafter Greuber).
Zollner teaches Ewing sarcoma (ES), a highly aggressive bone and soft-tissue cancer that by definition has micrometastatic disease at diagnosis and a dismal prognosis for patients with macrometastatic or recurrent disease (Abstract; Pg. 2, first full paragraph). Zollner teaches the early diagnosis of ES remains challenging since pseudo tumoral and benign bone lesions occur more frequently (Pg. 3, first full paragraph). Zollner teaches the initial staging to be key to both local and systemic therapy and follow-up care (Pg. 3, second full paragraph). Zollner teaches care of patients with relapsed ES remains a significant challenge and must be individualized for each patient’s disease and goals of care (Pg. 24, first paragraph). Zollner teaches that no new drugs have been successfully introduced to newly diagnosed patients for almost 40 years (Pg. 26, last paragraph). Zollner teaches a mechanism-based approach may be a way to improve treatment outcomes, and notes that a number of kinase inhibitors have been tested for ES but none of these have been successful in phase 2 evaluation (Pg. 27, first paragraph). Zollner teaches that several targeted therapies have been evaluated but none of these are currently part of standard therapy (Pg. 27, third paragraph). Zollner teaches that diagnostic, prognostic and therapeutic biomarkers are not yet well established for ES, especially because it is a rare disease (Pg. 37, last paragraph; Pg. 40, first paragraph). Zollner concludes that many aspects of ES remain elusive and emphasizes that a more personalized treatment may be desirable (Pg. 40, second paragraph).
Greuber suggest that drugs targeting ABL kinases may have utility in treating selected solid tumors due to enhanced expression and activation of these kinases in some solid tumors (Abstract). Greuber teaches the ABL family of protein kinases comprised of ABL1 and ABL2 (ARG), function to link diverse extracellular stimuli to signaling pathways controlling cell growth, survival, invasion, adhesion, and migration (Pg. 1, last paragraph). Greuber teaches several FDA-approved drugs targeting ABL kinases including imatinib and dasatinib have been tested for the treatment of solid tumors with mixed effectiveness; potentially due to the complexity of signaling pathways activated in solid tumors, the emergence of therapy resistance, and the fact that these inhibitors have multiple cellular targets (Pg. 2, continued paragraph). Greuber teaches ABL1 and ABL2 function redundantly in some cellular contexts, but also have unique roles, owing to distinct and conserved sequences and structural domains (Pg. 2, second full paragraph, Fig. 1). Greuber teaches the catalytic activities of the ABL kinases are tightly regulated by inter- and intramolecular interactions and post-translational modifications (Pg. 2, last paragraph; Fig. 1B). Greuber teaches that the application of TKIs in solid tumors is complex because ABL kinases can promote invasion and growth in some contexts while acting as tumor suppressors or functioning via diverse, context-dependent signaling networks in others (Pg. 6, first full paragraph).
Applicants are claiming a method of treating a subject having Ewing's sarcoma, the method comprising the step of administering to the subject a therapeutic combination comprising SP-2577 and an ABL inhibitor. Due to the unpredictability in the field of treating Ewing sarcoma (ES), a highly aggressive bone and soft-tissue cancer, as well as complexity with respect to treating solid tumors with ABL family kinases, as illustrated above, it is impossible to understand how any combination of an ABL inhibitor with SP-2577 would be capable of treating ES, a rare disease lacking established biomarkers.
The level of one of ordinary skill in the art
The relative level of skill in the art is high, such as, an oncologist or molecular biologist with advanced educational degrees (e.g., M.D. and/or Ph.D.). Additionally, there is significant unpredictability in the art regarding the development of therapies for the treatment of Ewing’s sarcoma.
The amount of direction provided by the inventor/The existence of working examples
The specification does not provide sufficient guidance/protocols for a skilled artisan to practice the claimed method of treating a subject having Ewing's sarcoma comprising the step of administering to the subject a therapeutic combination comprising SP-2577 and an ABL inhibitor, in its full scope. The instant specification discloses the results of a combination of SP-2577 and siABL2 for relative protein expression of cleaved Caspase 3 protein (Para. [0080]; FIG. 7A and 7B). The instant specification discloses additive effects for the combination of SP-2577 and Dasatinib against Ewing’s sarcoma cell lines (Para. [0085]; FIG 13A and 13B).
However, the disclosure does not indicate how the disclosed data correlates with the treatment of Ewing’s sarcoma using a combination of SP-2577 with any ABL inhibitor being claimed broadly. Different ABL inhibitors would require vastly different dosing strategies to achieve synergy in a combination. Thus, one of ordinary skilled in the art would not be able to practice the method of the instant claims to achieve the intended result in its claimed scope.
The quantity of experimentation needed
An unduly extensive amount of experimentation would be required for one of ordinary skill in the art to develop protocols for the claimed vast array of ABL inhibitors in the claimed pharmaceutical combination for treating Ewing’s sarcoma. The prior art demonstrates that different ABL inhibitors behave differently in solid tumors (e.g., varying off-target effects, resistance profiles, or cell-line specificities).
Generally, oncology and combination therapies are considered highly unpredictable arts. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
Considering the state of the art as discussed above, particularly with regards to the high degree of unpredictability in the art with respect to the treatment of Ewing’s sarcoma and application of kinase inhibitors to solid tumors, compounded with the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in scope with the claims.
Claim Rejections - 35 USC § 112 - Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(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 9-15 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 Ewing’s sarcoma and breast cancer a subject, using a pharmaceutical combination of SP-2577 and a composition selected from the group consisting of Ruxolitinib, Dasatinib, Nilotinib, Imatinib, Bosutinib, and a drug targeting ABL2 pathway, does not reasonably provide enablement for a method of treating any cancer in a subject using the pharmaceutical combination being broadly claimed. 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. This is a scope of enablement rejection.
To be enabling, 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, 1561 (Fed. Cir. 1993). The determination that "undue experimentation” would have been needed to practice the claimed invention in full scope is not a single, simple factual determination.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In re Wands, 8 USPQe2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
(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.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons:
The breadth of the claims/The nature of the invention
The claims recite a method of treating cancer in a subject, comprising the steps of: administering to the subject a therapeutically effective amount of SP-2577; and administering to the subject a therapeutically effective amount of a first pharmaceutical composition selected from the group consisting of Ruxolitinib, Dasatinib, Nilotinib, Imatinib, Bosutinib, and a drug targeting ABL2 pathway. The claim is drawn broadly to treating any cancer with the method of the instant claims. Therefore, the scope of the conditions being treated by the method claims is extensive, and encompass each and every type of cancer.
The state of the prior art/The level of predictability in the art
Lovly et al. (Tumor Heterogeneity and Therapeutic Resistance, 2016, hereinafter Lovly).
Lovly teaches tumor heterogeneity encompasses more than just the clinical picture and can represent both intratumor and intertumor differences (Abstract). Lovly teaches tumor heterogeneity is not one distinct term but rather encompasses several facets – within a disease, within a patient and within a tumor itself - that render tumors unique (Pg. e585, first column, last paragraph; Pg. e591, second column, first full paragraph). Lovly teaches ongoing challenges include the accurate and timely assessment of genetic changes as well as the development of resistance and the resultant compensatory mechanisms (Abstract; Pg. e586, second column, second full paragraph). Lovly, highlights the complexity of tumor heterogeneity in clinical decision making (e589-e590, case studies) and emphasizes that the need to understand the underlying causes of this heterogeneity and development of resistance, to effect better treatment outcomes (Pg. e591, second column, first full paragraph; Pg. e590, first column, first paragraph).
Therefore, it is clear that the significant variability found within and between tumors is a major contributor to treatment failure and cancer recurrence in patients. It is unclear how the instantly claimed method would achieve treatment/prevention of any and all types of cancers encompassed by the method claims, considering that different types of cancers have different etiologies with unique genetic/proteomic profiles requiring targeted therapies.
The level of one of ordinary skill in the art
The relative level of skill in the art is high, such as, an oncologist or molecular biologist with advanced educational degrees (e.g., M.D. and/or Ph.D.). Additionally, there is significant unpredictability in the art regarding the development of therapies, due to the heterogenous nature of cancers.
The amount of direction provided by the inventor/The existence of working examples
The instant specification discloses the results of a combination of SP-2577 and siABL2 for relative protein expression of cleaved Caspase 3 protein (Para. [0080]; FIG. 7A and 7B). The instant specification discloses additive effects for the combination of SP-2577 and Dasatinib against Ewing’s sarcoma cell lines (Para. [0085]; FIG 13A and 13B). The instant specification discloses results for silencing of FOXR2 gene in breast cancer cell lines (Paras. [0087]-[0089].
However, the disclosure does not indicate how the disclosed data correlates with the treatment of all cancers being claimed. There is lack of direction or guidance regarding how the administration of the disclosed combination therapy is capable of treating all types of cancers. One of ordinary skilled in the art would not be able to practice the method of the claims to achieve the intended result of treating each and every type of cancer.
The quantity of experimentation needed
Considering the state of the art as discussed above, particularly with regards to the high degree of unpredictability in the art with respect to treating various tumors and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in scope with the claims.
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 14-15 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.
Regarding claim 14, the claim depends from claim 9 and recites “wherein one or both of the first pharmaceutical composition and the second pharmaceutical composition are administered as a gas or aerosol”. However, claim 9 does not recite “second pharmaceutical composition”. There is insufficient antecedent basis for this limitation in the claim.
For the purpose of applying prior art, claim 14 has been interpreted to read “wherein one or both of the SP-2577 and the first pharmaceutical composition [[and the second pharmaceutical composition ]]are administered as a gas or aerosol”.
Regarding claim 15, the claim depends from claim 9 and recites “wherein the one or both of the first pharmaceutical composition and the second pharmaceutical composition are administered as solutions, …”. However, claim 9 does not recite “second pharmaceutical composition”. There is insufficient antecedent basis for this limitation in the claim.
For the purpose of applying prior art, claim 15 has been interpreted to read “wherein the one or both of the SP-2577 and the first pharmaceutical composition [[and the second pharmaceutical composition ]]are administered as solutions, …”.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 3-15 are rejected under 35 U.S.C. 103 as being unpatentable over Sampson et al. (Abstract 1175: Identification of novel combination therapies with the LSD1 inhibitor SP-2577 (Seclidemstat) in Ewing's Sarcoma using a complete druggable CRISPR library approach, 01 July 2021, hereinafter Sampson, in the IDS) in view of Blumberg et al. (WO 2022/020804 A1, filing date 26 July 2021, hereinafter Blumberg.
Blumberg qualifies as 102(a)(2) prior art with an effectively filed date of 26 July 2021, that precedes the effective filing date of the instant invention 20 October 2021.
Regarding instant claims 1 and 4, Sampson teaches novel combination therapies with the LSD1 reversible inhibitor, SP-2577 (the instantly claimed species of first therapeutic agent), to help increase the cytotoxicity of the drug within Ewing’s sarcoma (ES) cell types (Title; Abstract, Introduction paragraph). Sampson teaches a drug combination treatment of SP-2577 with Ruxolitinib or Dasatinib in ES cell lines showed high synergy at low dose ratio (this teaches the step of administering the combination treatment in an in vitro method) (Abstract, Results paragraph) and highlights the potential of the combination in the treatment of ES patients (Abstract, Conclusion paragraph).
According to MPEP 2112.01(II), "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In the instant case, Sampson teaches a combination therapy of SP-2577 with Dasatinib in ES cell lines. Dasatinib, by virtue of their inherent property, is an ABL pathway inhibitor.
Sampson do not explicitly teach administering the combination therapy in a subject having Ewing’s sarcoma and pharmaceutical compositions of SP-2577 and the ABL inhibitor, Dasatinib.
Blumberg teaches SP-2577 as a small molecule LSD1 inhibitor (Para. [0006]). Blumberg teaches pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a LSD1 inhibitor compound (Para. [0015]). Blumberg teaches a methods and compositions for treating a disease or disorder associated with an LSD1 activity dysfunction in a mammal comprising the step of administering to the mammal a therapeutically effective amount of a LSD1 inhibitory compound (Para. [0059]; Para. [0062]; Paras. [0065]-[0066]; Para. [0077]). Blumberg teaches disorders associated with an LSD1 activity dysfunction to include cancers, wherein the cancer is a sarcoma or bone cancer (Paras. [0069]-[0071]). Blumberg teaches combination therapies with other agents (Paras. [0079]-[0081]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Sampson and Blumberg, to have applied the in vitro method of Sampson to the treatment of Ewing’s sarcoma in a subject afflicted with the condition, by administering the combination therapy as a pharmaceutical composition, to arrive at the method of the instant claims with a reasonable expectation of success.
Sampson teaches novel combination therapies with the LSD1 reversible inhibitor, SP-2577, to help increase the cytotoxicity of the drug within Ewing’s sarcoma (ES) cell types. Sampson teaches a drug combination treatment of SP-2577 with Ruxolitinib or Dasatinib (i.e., ABL pathway inhibitors) in ES cell lines showed high synergy at low dose ratio. Sampson explicitly provides motivation for use of the combination in the treatment of ES patients. Blumberg teaches SP-2577 as a small molecule LSD1 inhibitor, pharmaceutical compositions thereof. Blumberg teaches methods for treating cancers, specifically sarcomas, in a mammal comprising the step of administering to the mammal a therapeutically effective amount of a LSD1 inhibitory compound, say SP-2577.
Therefore, one of ordinary skill in the art would have been motivated to apply the method of Sampson to the treatment of Ewing’s sarcoma in a subject. Doing so would have been well within the skill of one of ordinary skill in the pharmaceutical arts. The teachings of Sampson and Blumberg render obvious the limitations of instant claim 1 drawn broadly to a combination of SP-2577 and an ABL inhibitor AND the limitations of instant claim 4.
Regarding instant claim 3, the combined teachings of Sampson and Blumberg render obvious the method of instant claim 1. Sampson do not explicitly teach wherein the subject is human.
Blumberg teaches the subject to be a human (Paras. [0039]-[0040]). Therefore, one of ordinary skill in the art would have been motivated to apply the combination of SP-2577 and a ABL inhibitor in the treatment of Ewing’s sarcoma in a human subject. The motivation being to potentiate the cytotoxicity of the drug, SP-2577, within ES cell types for optimal therapeutic effect (Sampson, Abstract, Introduction paragraph).
Regarding instant claims 5-6, the combined teachings of Sampson and Blumberg render obvious the method of instant claim 1. Sampson do not explicitly teach wherein the first pharmaceutical composition and the second pharmaceutical composition are administered concurrently/sequentially.
Blumberg teaches combination therapy wherein the agents can be administered concurrent to, or subsequent to the administration of other agent(s) (Para. [0083]). Absent any criticality of the order of administration, a PHOSITA would have been motivated to administer the two compositions of SP-2577 and the ABL inhibitor either concurrently or sequentially, with a reasonable expectation of success. Therefore, the limitations of instant claims 5-6 are rendered prima facie obvious.
Regarding instant claim 7, the combined teachings of Sampson and Blumberg render obvious the method of instant claim 1. Sampson do not explicitly teach wherein one or both of the first pharmaceutical composition and the second pharmaceutical composition are administered as a gas or aerosol.
Blumberg teaches “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Blumberg teaches such method to include administration by inhalation, nasal administration (Para. [0044]).
According to MPEP 2144.05(II)(A), "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."
Absent any criticality of the route of administration, a PHOSITA would have been motivated to administer the two compositions of SP-2577 and the ABL inhibitor via a suitable route of administration, say inhalation (as a gas or aerosol), with a reasonable expectation of success. Doing so would have been well within the skill of one of ordinary skill in the pharmaceutical arts, through routine experimentation. Therefore, the limitations of instant claim 7 is rendered prima facie obvious.
. Regarding instant claim 8, the combined teachings of Sampson and Blumberg render obvious the method of instant claim 1. Sampson do not explicitly teach wherein one or both of the first pharmaceutical composition and the second pharmaceutical composition are administered as solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules including liquids, powders, sustained-release formulations, directed release formulations, lyophylates, suppositories, emulsions, aerosols, sprays, granules, powders, syrups, or elixirs.
Blumberg teaches the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient (Para, [0086]). Blumberg teaches the “pharmaceutically acceptable carrier” can include solutions, dispersions, suspensions or emulsions (Para. [0052]). This renders the pharmaceutical dosage forms of instant claim 8 prima facie obvious.
Ewing’s sarcoma is a highly aggressive bone and soft-tissue cancer. Therefore, the combined teachings of Sampson and Blumberg renders obvious the limitations of instant independent claim 9, drawn to a method of treating cancer in a subject, by administering a combination therapeutic as instantly claimed, and the dependent claims 10-15. The citations and rationale applied to claims 1 and 3-8 above, apply to claims 9-15 as well.
Applicant may rely on the exception under 35 U.S.C. 102(b)(1)(A) to overcome this rejection under 35 U.S.C. 102(a)(1) by a showing under 37 CFR 1.130(a) that the subject matter disclosed in the Sampson reference was obtained directly or indirectly from the inventor or a joint inventor of this application, and is therefore not prior art under 35 U.S.C. 102(a)(1).
Claims 1 and 3-15 (regarding the instantly elected species of combination therapeutic) are rejected under 35 U.S.C. 103 as being unpatentable over Sampson et al. (Abstract 1175: Identification of novel combination therapies with the LSD1 inhibitor SP-2577 (Seclidemstat) in Ewing's Sarcoma using a complete druggable CRISPR library approach, 01 July 2021, hereinafter Sampson, in the IDS) in view of Blumberg et al. (WO 2022/020804 A1, filing date 26 July 2021, hereinafter Blumberg) and Liu (US 2019/0201552 A1, publication date 04 July 2019).
Blumberg qualifies as 102(a)(2) prior art with an effectively filed date of 26 July 2021, that precedes the effective filing date of the instant invention 20 October 2021.
Regarding the instantly elected species of combination therapy with respect to claim 1, the teachings of Sampson and Blumberg are discussed in the rejection over the broader scope of claim 1 above and incorporated herein by reference. Sampson teaches an arrayed CRISPR screening identified 103 gene deletions that resulted in increased SP-2577 cytotoxicity, in an Ewing’s sarcoma cell line. Sampson two high-interest hits to have significant interaction with the LSD1 pathway as ABL2 and SH2B3 (Abstract, Results paragraph).
Sampson and Blumberg do not teach wherein the combination therapeutic comprises an agent that targets ABL2 pathway being siABL2 (the instantly claimed species of second therapeutic agent).
Liu teaches methods of using the aptamer compositions for selectively targeting cells to down-regulate the expression of specific genes in targeted cells (Abstract; Para. [0093]). Liu teaches the aptamer compositions comprise siRNAs that specifically inhibit or down-regulate expression of one or more genes, specifically oncogenes (Para. [0082]). Liu teaches representative oncogenes that can be down-regulated by the siRNA in the chimeras include ABL2 (Paras, [0084]-[0085]; Para. [0096]). Liu teaches the aptamer compositions are administered to a subject having or suspected of having cancer in an amount effective to inhibit expression of two or more genes in the cancer survival pathway (Para. [0095]). Liu teaches the cancers that can be treated to include Ewing’s sarcoma (Para. [0097]). Liu teaches the aptamer compositions can be used in combination or alternation with a second therapeutic (Para. [0104]). Liu teaches sequence information for these oncogenes are known in the art, and one of skill in the art could readily make siRNA constructs to specifically inhibit oncogene expression (Para. [0085]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Sampson, Blumberg and Liu, to have utilized a combination therapeutic that comprises an agent that targets ABL2 pathway, say a siABL2, in the method of Sampson, to arrive at the method of the instant claims with a reasonable expectation of success. Sampson teaches novel combination therapies with the LSD1 reversible inhibitor, SP-2577 (the instantly claimed species of first therapeutic agent), to help increase the cytotoxicity of the drug within Ewing’s sarcoma (ES) cell types. Sampson teaches a drug combination treatment of SP-2577 with Ruxolitinib or Dasatinib (an ABL pathway inhibitor) in ES cell lines showed high synergy at low dose ratio (this teaches the step of administering the combination treatment in an in vitro method) and highlights the potential of the combination in the treatment of ES patients. Blumberg teaches SP-2577 as a small molecule LSD1 inhibitor and pharmaceutical compositions thereof for use in the treatment of cancers, wherein the cancer is a sarcoma or bone cancer. Blumberg teaches combination therapies with other agents. Liu teaches the aptamer compositions comprising siRNAs that specifically inhibit or down-regulate expression of one or more genes, specifically oncogenes. Liu teaches representative oncogenes that can be down-regulated by the siRNA in the chimeras include ABL2. Liu teaches the aptamer compositions are administered to a subject having or suspected of having cancer in an amount effective to inhibit expression of two or more genes in the cancer survival pathway. Liu teaches the cancers that can be treated to include Ewing’s sarcoma. Liu teaches the aptamer compositions can be used in combination or alternation with a second therapeutic. Liu teaches sequence information for these oncogenes are known in the art, and one of skill in the art could readily make siRNA constructs to specifically inhibit oncogene expression.
According to MPEP 2144.06 (I), "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). In the instant case, the composition of Sampson (comprising Dasatinib) and the composition of Liu (comprising siRNA for ABL2), are both taught to be anti-cancer therapeutics. Both of them teach targeting the ABL pathway and can therefore be combined to form a third composition that comprises a combination of SP-2577, Dasatinib and siRNA specifically designed to target the ABL2 gene, to arrive at the combination composition of the instant claims (the presence of the open-ended transitional phrase “comprising” in instant claim 1, allows for the inclusion of additional, unrecited elements).
Alternatively, one of ordinary skill in the art, would have been motivated to substitute the Dasatinib of Sampson with the siRNA specifically designed to target the ABL2 gene, as taught by Liu, to arrive at the composition of the instant claims.
As stated in MPEP 2144.06 (II), “An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)”. In the instant case, both Dasatinib and the siRNA specifically designed to target the ABL2 gene, are drugs targeting the ABL pathway that are considered equivalents in the art.
Therefore, one of ordinary skill in the art would have been motivated to include an siRNA in the method of Sampson OR substitute the Dasatinib in the method of Sampson, to arrive at the combination therapy of the instant method with a reasonable expectation of success. The motivation being to use an approach of targeted combination therapy with reduced off-target effects in the treatment of cancer (specifically, Ewing’s sarcoma), thereby improving treatment outcomes (Liu, Para. [0011]; Para. [0013]).
Furthermore, claims 3-8 and 9-15 are similarly rejected over the combination of Sampson, Blumberg and Liu, over the instantly elected species of combination therapy using the same rationale as applied in the rejection over Sampson in view of Blumberg.
Applicant may rely on the exception under 35 U.S.C. 102(b)(1)(A) to overcome this rejection under 35 U.S.C. 102(a)(1) by a showing under 37 CFR 1.130(a) that the subject matter disclosed in the Sampson reference was obtained directly or indirectly from the inventor or a joint inventor of this application, and is therefore not prior art under 35 U.S.C. 102(a)(1).
Claims 1, 3-4 and 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Reed et al. (Phase 1 trial of seclidemstat (SP-2577) in patients with relapsed/refractory Ewing sarcoma, published 28 May 2021, hereinafter Reed), Wang et al. (The Emerging Role of ABL Kinases in Solid Tumors, published online 01 October 2016, hereinafter Wang) and Liu (US 2019/0201552 A1, publication date 04 July 2019).
Regarding instant claims 1 and 3-4, Reed teaches a phase 1 trial of seclidemstat (SP-2577) in patients with relapsed/refractory Ewing sarcoma (ES) (Title; Abstract, Methods section). Reed teaches patients >12 years with relapsed or refractory (R/R) Ewing’s sarcoma received oral SP-2577 (i.e., a first pharmaceutical composition and the first agent in the elected species of combination therapeutic) twice daily in 28-day cycles under fasting conditions at the assigned dose level (Abstract, Methods section; Results section) (this reads on the limitations drawn to a method of treating a subject having ES as in instant claim 1; limitation of a human patient as in instant claim 3 and the limitations of instant claim 4 since an oral formulation inherently comprises one or more pharmaceutically acceptable excipients). Reed teaches SP-2577 had a manageable safety profile and demonstrated preliminary activity with respect to reduction in target lesions in subjects with relapsed/refractory ES (Abstract, Results paragraph; Conclusion paragraph). Reed suggests expansion of SP-2577 monotherapy in combination with chemotherapy for ES (Abstract, Conclusion paragraph).
Reed do not teach administering a second pharmaceutical composition comprising an ABL inhibitor, wherein the composition comprises an agent that targets ABL2 pathway, say an ABL2 knockdown agent, siABL2 (i.e., the instantly claimed species of second therapeutic agent).
Wang teaches the emerging role of ABL kinases in solid tumors (Title, Abstract). Wang teaches recent data generated from genomic and proteomic studies linking enhanced expression and hyper-activation of the ABL kinases in some human cancers (Abstract). Wang teaches activation of ABL kinases in solid tumors to be driven by enhanced ABL1 or ABL2 expression and/or activation due to amplification, increased gene expression, enhanced protein expression, and/or increased enzymatic activity in response to stimulation by oncogenic tyrosine kinases (Pg. 5, first full paragraph). Wang teaches that ABL kinases play a role in cancer cell invasion and metastasis (Pg. 7, last paragraph – Pg. 8, first full paragraph) and development of intrinsic or acquired drug resistance (Pg. 8, last paragraph – Pg. 9, continued paragraph). Wang teaches cancers with ABL hyperactivation may benefit from treatment with ABL-selective inhibition (Pg. 10, first paragraph). Wang attributes the low success of tyrosine kinase inhibitors (TKIs) in solid tumors to activation of proliferative pathways as a result of unintended targeting of other kinases (Pg. 9, last paragraph). Wang teaches combination therapy in addition to ABL inhibition as a promising strategy to impair metastatic progression and prevent the development of chemoresistance in selected solid tumors (Pg. 15, Trends Box).
Liu teaches methods of using the aptamer compositions for selectively targeting cells to down-regulate the expression of specific genes in targeted cells (Abstract; Para. [0093]). Liu teaches the aptamer compositions comprise siRNAs that specifically inhibit or down-regulate expression of one or more genes, specifically oncogenes (Para. [0082]). Liu teaches representative oncogenes that can be down-regulated by the siRNA in the chimeras include ABL2 (Paras, [0084]-[0085]; Para. [0096]). Liu teaches the aptamer compositions are administered to a subject having or suspected of having cancer in an amount effective to inhibit expression of two or more genes in the cancer survival pathway (Para. [0095]). Liu teaches the cancers that can be treated to include Ewing’s sarcoma (Para. [0097]). Liu teaches the aptamer compositions can be used in combination or alternation with a second therapeutic (Para. [0104]). Liu teaches sequence information for these oncogenes are known in the art, and one of skill in the art could readily make siRNA constructs to specifically inhibit oncogene expression (Para. [0085]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Reed, Wang and Liu, to have utilized a combination therapeutic that comprises SP-2577 as taught by Reed and an agent that targets ABL2 pathway, say a siABL2 as taught by Liu, in the method of Reed, to arrive at the method of the instant claims with a reasonable expectation of success. Reed teaches a phase 1 trial of seclidemstat (SP-2577) in patients with relapsed/refractory Ewing sarcoma (ES). Reed teaches patients >12 years with relapsed or refractory (R/R) Ewing’s sarcoma received oral SP-2577 (i.e., the first agent in the elected species of combination therapeutic) twice daily in 28-day cycles under fasting conditions at the assigned dose level. Blumberg teaches SP-2577 as a small molecule LSD1 inhibitor and pharmaceutical compositions thereof for use in the treatment of cancers, wherein the cancer is a sarcoma or bone cancer. Wang teaches the emerging role of ABL kinases in solid tumors. Wang teaches recent data generated from genomic and proteomic studies linking enhanced expression and hyper-activation of the ABL kinases in some human cancers. Wang teaches activation of ABL kinases in solid tumors to be driven by enhanced ABL1 or ABL2 expression and/or activation due to amplification, increased gene expression, enhanced protein expression, and/or increased enzymatic activity in response to stimulation by oncogenic tyrosine kinases. Wang teaches cancers with ABL hyperactivation may benefit from treatment with ABL-selective inhibition. Wang teaches combination therapy in addition to ABL inhibition as a promising strategy to impair metastatic progression and prevent the development of chemoresistance in selected solid tumors. Liu teaches the aptamer compositions comprising siRNAs that specifically inhibit or down-regulate expression of one or more genes, specifically oncogenes. Liu teaches representative oncogenes that can be down-regulated by the siRNA in the chimeras include ABL2. Liu teaches the aptamer compositions are administered to a subject having or suspected of having cancer in an amount effective to inhibit expression of two or more genes in the cancer survival pathway. Liu teaches the cancers that can be treated to include Ewing’s sarcoma. Liu teaches the aptamer compositions can be used in combination or alternation with a second therapeutic. Liu teaches sequence information for these oncogenes are known in the art, and one of skill in the art could readily make siRNA constructs to specifically inhibit oncogene expression.
According to MPEP 2144.06 (I), "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). In the instant case, the composition of Reed and the composition of Liu, are both taught to be anti-cancer therapeutics for use in the treatment of Ewing’s sarcoma. Therefore, the two compositions can be combined to form a third composition that comprises a combination of SP-2577 and siRNA specifically designed to target the ABL2 gene (in view of the teachings of Wang), to arrive at the combination composition of the instant claims for use in a method of treating Ewing’s sarcoma in a subject.
Ewing’s sarcoma is a highly aggressive bone and soft-tissue cancer. Therefore, the combined teachings of Reed, Wang and Liu renders obvious the limitations of instant independent claim 9, drawn to a method of treating cancer in a subject and the dependent claims 10-11. The citations and rationale applied to claims 1 and 3-4 above, apply to claims 9-11 as well.
Claims 5-8 and 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Reed et al. (Phase 1 trial of seclidemstat (SP-2577) in patients with relapsed/refractory Ewing sarcoma, published 28 May 2021, hereinafter Reed), Wang et al. (The Emerging Role of ABL Kinases in Solid Tumors, published online 01 October 2016, hereinafter Wang) and Liu (US 2019/0201552 A1, publication date 04 July 2019) as applied to claims 1, 3-4 and 9-11 above, and further in view of in view of Blumberg et al. (WO 2022/020804 A1, filing date 26 July 2021, hereinafter Blumberg).
The teachings of Reed, Wang and Liu are set forth in the obviousness rejection above and incorporated herein by reference.
Regarding instant claims 5-8 and 12-15, the combined teachings of Reed, Wang and Liu render the method of instant claim 1 and instant claim 9 prima facie obvious.
Reed, Wang and Liu do not teach wherein the first pharmaceutical composition and the second pharmaceutical composition are administered concurrently OR sequentially; wherein one or both of the first pharmaceutical composition and the second pharmaceutical composition are administered as formulations recited in instant claims 7-8 and 14-15.
Blumberg teaches combination therapy wherein the agents can be administered concurrent to, or subsequent to the administration of other agent(s) (Para. [0083]). Blumberg teaches “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Blumberg teaches such method to include administration by inhalation, nasal administration (Para. [0044]). Blumberg teaches the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient (Para, [0086]). Blumberg teaches the “pharmaceutically acceptable carrier” can include solutions, dispersions, suspensions or emulsions (Para. [0052]).
According to MPEP 2144.05(II)(A), "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."
Absent any criticality of the order of administration or the route of administration, a PHOSITA would have been motivated to administer the two compositions of SP-2577 and the ABL inhibitor either concurrently or sequentially, and via a suitable route of administration, say inhalation (as a gas or aerosol), with a reasonable expectation of success. Doing so would have been well within the skill of one of ordinary skill in the pharmaceutical arts, through routine experimentation. Therefore, the limitations of instant claims 5-8 and 12-15 are rendered prima facie obvious.
Conclusion
Claims 1 and 3-15 are rejected.
No claims are allowed.
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/PADMAJA S RAO/Examiner, Art Unit 1627
