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 Claims
Claims 1-20 are currently pending and under examination.
Claim Objections
Claims 4-5, 9-13, and 17-20 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim shall not serve as a basis for any other multiple dependent claims. See MPEP § 608.01(n). Accordingly, the claims 4-5, 9-13, and 17-20 have not been further treated on the merits.
Claim 1 is objected to because of the following informalities: “adminstering” should read administering.
Claims 2-3, 7-8, and 15-16 are objected to because of the following informalities: A comma is required after the preamble of a dependent claim, and before a further limitation is introduced. For example: In claims 2, 7, and 15, “The method of claim…wherein” should read: The method of claim …, wherein. In claims 3, 8, and 16, “The method of claim… in which” should read: The method of claim…, in which.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 6, 7, 8, 14, 15, and 16 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 methods of treating a malignant peripheral nerve sheath tumor comprising administering to a patient in need thereof, a therapeutically effective amount of the SHP2 inhibitor TNO155, TNO155 with one of CDK4/6 inhibitors ribociclib or palbociclib, and either ribociclib or palbociclib with the MEK inhibitor trametinib, does not reasonably provide enablement for methods of treating a malignant peripheral nerve sheath tumor comprising administering to a patient in need thereof, any and all SHP2 inhibitors, either alone or in combination with any and all CDK4/6 inhibitors, and any and all CDK4/6 inhibitors in combination with any and all MEK inhibitors. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: 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 regard to the instant claims, with the most relevant factors discussed below.
Nature of the Invention: Claim 1 is drawn to a method of treating a malignant peripheral nerve sheath tumor comprising administering to a patient in need thereof a therapeutically effective amount of a SHP2 inhibitor. Claim 6 is drawn to a method of treating a malignant peripheral nerve sheath tumor comprising administering to a patient in need thereof a pharmaceutical composition comprising: (a) a SHP2 inhibitor; and (b) a CDK4/6 inhibitor. Claim 14 is drawn to a method of treating a malignant peripheral nerve sheath tumor comprising administering to a patient in need thereof a pharmaceutical composition comprising: (a) a MEK inhibitor; and (b) a CDK4/6 inhibitor.
However, the nature of the invention is complex in that the efficacy of the claimed SHP2 inhibitors, CDK4/6 inhibitors, and MEK inhibitors, in the context of the claimed methods, other than the select species TNO155, ribociclib, palbociclib, and trametinib, has not been demonstrated.
Breadth of the Claims: The claims are broad in that the claims recite methods of treating a malignant peripheral nerve sheath tumor comprising administering to a patient in need thereof, a therapeutically effective amount of any and all SHP2 inhibitors, either alone or in combination with any and all CDK4/6 inhibitors, and any and all CDK4/6 inhibitors in combination with any and all MEK inhibitors. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the Specification and Existence of Working Examples: The specification demonstrates treatment of mice grafted with MPNST cells with administration of TNO155, alone and in combination with ribociclib, as well as ribociclib in combination with trametinib. Kohlmeyer demonstrates administration of palbociclib to mice with grafted human MPNST cells. However, no working examples are given for treatment of MPNST by administering any and all SHP2 inhibitors, either alone or in combination with any and all CDK4/6 inhibitors, and any and all CDK4/6 inhibitors in combination with any and all MEK inhibitors. While it is noted that the applicant has shown some data for activity against relevant cell lines with select compounds, the applicant is not enabled for treatment of MPNST by administering any and all SHP2 inhibitors, either alone or in combination with any and all CDK4/6 inhibitors, and any and all CDK4/6 inhibitors in combination with any and all MEK inhibitors.
Predictability and State of the Art: The state of the art at the time the invention was made was unpredictable and underdeveloped. It is known in the art that MPNST is a rare form of cancer, as taught by Nagabushan (See page 1; Introduction).
National Institute of Health. Malignant Peripheral Nerve Sheath Tumor, [retrieved on 02/06/2026]. www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-soft-tissue-tumors/mpnst. (Year: 2020) - teaches that Sarcomas are rare cancers, and MPNST is a rare type of sarcoma, making up 5% to 10% of sarcoma cases.
Amount of Experimentation Necessary: The quantity of experimentation necessary to carry out the claimed invention is high, as the skilled artisan could not rely on the prior art or instant specification to teach methods of treating a malignant peripheral nerve sheath tumor comprising administering to a patient in need thereof, any and all SHP2 inhibitors, either alone or in combination with any and all CDK4/6 inhibitors, and any and all CDK4/6 inhibitors in combination with any and all MEK inhibitors.
In order to carry out the claimed invention, one of ordinary skill in the art would have to administer all of the claimed SHP2 inhibitors, CDK4/6 inhibitors, and MEK inhibitors currently known in the art, as well as all future discovered compounds in these classes, to subjects with MPNST, and determine efficacy.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 1, 2, 6, 7, 14 and 15 are not considered to be fully enabled by the instant specification.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 14-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nagabushan, S. (Efficacy of MEK inhibition in a recurrent malignant peripheral nerve sheath tumor), Precision Oncology, Vol. 5, no. 9, pp. 1-6 (Year: 2021), in view of
Kohlmeyer, J. (RABL6A Is an Essential Driver of MPNSTs that Negatively
Regulates the RB1 Pathway and Sensitizes Tumor Cells to CDK4/6 Inhibitors, Clinical Cancer Research, Vol.26, no. 12, pp. 2997-3011 (Year: 2020)).
Nagabushan teaches a method of administering the Applicant’s claimed MEK inhibitor, N-(3-(3-cyclopropyl-5-((2- fluoro-4-iodophenyl)amino)-6, 8-dimethyl-2,4,7-trioxo-3,4,6,7 tetrahydropyrido [4,3- d]pyrimidin-1(2H)-yl)phenyl)acetamide, also known as trametinib, to a human subject with MPNST (See page 1; introduction), and that this treatment resulted in a sustained complete response of greater than 15 months. Nagabushan also teaches that the subject of the method taught did not have history or features of NF1 or prior radiotherapy, and thus the MPNST was sporadic as defined by the Applicant and as is understood in the art. The Applicant’s limitations of the MPNST being either sporadic, associated with neurofibromatosis type 1, or associated with radiotherapy, are obvious as any instance of known MPNST falls within one of these categories.
However, Nagabushan does not teach a method of administrating a CDK4/6 inhibitor.
Kohlmeyer teaches a method of administering a CDK4/6 inhibitor, palbociclib (See page 2997; Results), to a mice grafted with human MPNST cell lines (See page 2999; Cell culture), suppressing MPNST growth.
It would have been obvious to one having ordinary skill in the art, before the Applicant’s effective filling date, to combine Nagabushan’s teaching of administering trametinib as a MEK inhibitor to a subject with MPNST that is either sporadic, associated with neurofibromatosis type 1 or associated with radiotherapy, with Kohlmeyer’s teaching of administering palbociclib as an CDK4/6 inhibitor to mice with human MPNST cell lines.One having ordinary skill in the art would have had sufficient teaching, suggestion, or motivation, to combine Nagabushan’s teaching of administering trametinib as a MEK inhibitor to a subject with MPNST that is either sporadic, associated with neurofibromatosis type 1 or associated with radiotherapy, with Kohlmeyer’s teaching of administering palbociclib as an CDK4/6 inhibitor to mice with human MPNST cell lines, with a reasonable expectation of success in arriving at the Applicant’s claimed method of treating a malignant peripheral nerve sheath tumor comprising administering to a patient in need thereof a pharmaceutical composition comprising: (a) a MEK inhibitor; and (b) a CDK4/6 inhibitor, wherein the malignant peripheral nerve sheath tumor is sporadic, associated with neurofibromatosis type 1 or associated with radiotherapy, and wherein the MEK inhibitor is N-(3-(3-cyclopropyl-5-((2- fluoro-4-iodophenyl)amino)-6, 8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido [4,3- d]pyrimidin-1(2H)-yl)phenyl)acetamide (trametinib), or pharmaceutically acceptable salt thereof.
Double Patenting
The non-statutory 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 non-statutory 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 non-statutory 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 non-statutory 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.
(Of Note: The following double patenting rejections are PROVISIONAL)
Claims 1-3 and 6-8 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over the following claims of co-pending Application No. 18/839,600: 16 (for present claims 1-3, and 6-8, in view of Nagabushan, S. (Efficacy of MEK inhibition in a recurrent malignant peripheral nerve sheath tumor), Precision Oncology, Vol. 5, no. 9, pp. 1-6 (Year: 2021) in view of
Kohlmeyer, J. (RABL6A Is an Essential Driver of MPNSTs that Negatively
Regulates the RB1 Pathway and Sensitizes Tumor Cells to CDK4/6 Inhibitors), Clinical Cancer Research, Vol.26, no. 12, pp. 2997-3011 (Year: 2020).
(Of Note: This rejection will support the rejections that follow below where applicable.)
Although the claims are not identical, they are not patentably distinct from one another because the claims of the co-pending application are also drawn to the same compound and method of the instant application.
The co-pending claim 16 is drawn to the same compound (TNO155 and corresponding names and structures) and formulations thereof, used in comparable methods of administration to a subject in need thereof.
Notable limitations in the method of the Applicant that are not in that of the co-pending include the MPNST being metastatic, unresectable, sporadic, associated with neurofibromatosis type 1 or associated with radiotherapy, and the addition of a CDK4/6 inhibitor to the method alongside a SHP2 inhibitor.
However, the limitations of the MPNST being metastatic, unresectable, sporadic, associated with neurofibromatosis type 1 or associated with radiotherapy are obvious subcategories that collectively comprise MPNST as a whole. Kohlmeyer teaches that NF1 patients are at higher risk of MPNST development than the general population (See page 2997; Introduction). Nagabushan teaches that the patient treated in their method had a metastatic MPNST (See page 1; Introduction).
The addition of a CDK4/6 inhibitor to a method using and SHP2 inhibitor to treat MPNST is obvious as CDK4/6 inhibitors were already known in the art to be effective in treating MPNST. Kohlmeyer teaches that palbociclib, a CDK4/6 inhibitor, showed activity against human MPNST cell lines grafted in mice (See page 2997; Results).
It would have been prima facie obvious to one skilled in the art to arrive at the Applicant’s instant claims, in view of the claims of co-pending application 18/839,600, and Nagabushan, S. (Efficacy of MEK inhibition in a recurrent malignant peripheral nerve sheath tumor), Precision Oncology, Vol. 5, no. 9, pp. 1-6 (Year: 2021) in view of
Kohlmeyer, J. (RABL6A Is an Essential Driver of MPNSTs that Negatively
Regulates the RB1 Pathway and Sensitizes Tumor Cells to CDK4/6 Inhibitors), Clinical Cancer Research, Vol.26, no. 12, pp. 2997-3011 (Year: 2020)
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/OROD MOTEVALLI/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628