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 Rejections - 35 USC § 112(a)
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 50, 52 and 55-82 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 desmoid tumor where such treatment does not encompass the prevention of such tumors, does not reasonably provide enablement for a method which does encompass the prevention of such tumors. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
With regard to rejections under 35 USC 112(a) or 35 USC 112, first paragraph, the following factors are considered (MPEP 2164.01(a)): a) Breadth of claims; b) Nature of invention; c) State of the prior art; d) Level of ordinary skill in the art; e) Level of predictability in the art; f) Amount of direction and guidance provided by the inventor; g) Working examples and; h) Level of experimentation needed to make or use the invention based on the content of the disclosure.
a)The claims are extraordinarily broad: “A method for treating desmoid tumor in a patient…where (i) the patient previously was treated for desmoid tumor with 150 mg (free base equivalent dose) of nirogacestat or a pharmaceutically acceptable salt thereof orally twice daily and, during such prior treatment, experienced an…(ALT) or…(AST) of 3 to 5 times upper limit of normal (ULN) and (ii) the ALT, AST, or both are resolved to less than 3 times ULN or baseline, the method comprising orally administering to the patient 100 mg (free base equivalent dose) of nirogacestat or a pharmaceutically acceptable salt twice daily” (independent claim 50).
“A method for treating desmoid tumor in a patient…where (i) the patient previously was treated for desmoid tumor with 150 mg (free base equivalent dose) of nirogacestat or a pharmaceutically acceptable salt thereof orally twice daily and, during such prior treatment, experienced Grade 3 or 4 hypokalemia despite maximal replacement therapy and (ii) the hypokalemia is resolved to no higher than Grade 1 hypokalemia or baseline, the method comprising orally administering to the patient 100 mg (free base equivalent dose) of nirogacestat or a pharmaceutically acceptable salt twice daily” (independent claim 52). Dependent claims 57-82 further define the method and the patient.
“A method for treating desmoid tumor in a patient…where (i) the patient previously was treated for desmoid tumor with 150 mg (free base equivalent dose) of nirogacestat or a pharmaceutically acceptable salt thereof orally twice daily and, during such prior treatment, experienced Grade 3 or 4 hypophosphatemia despite maximal replacement therapy and (ii) the hypophosphatemia is resolved to no higher than Grade 1 hypophosphatemia or baseline, the method comprising orally administering to the patient 100 mg (free base equivalent dose) of nirogacestat or a pharmaceutically acceptable salt twice daily” (independent claim 55). Dependent claim 56 further defines the method.
The examiner notes that the specification explicitly states that the term treating encompasses prophylactic and preventative treatment (page 24, [0124]).
b,c) The nature of the invention is determined in part by the state of the prior art.
As even a cursory perusal of the medicinal arts reveals, they have not advanced to the point where complex diseases, with a significant genetic component, such as desmoid tumors (i.e. cancer), can be said to be prevented.
d) The level of skill in the art is considered to be relatively high.
e) The level of predictability in the art is considered to be relatively low.
The basis of all modern medicine and biology is, of course, chemistry. Yet even under the best of circumstances, and more than two hundred years after Lavoisier laid the foundations of its modern practice, chemistry remains an experimental science. Neither the medicinal/biological arts nor the chemical arts upon which they are based have advanced to the point where certainty has replaced the need for clinical and/or laboratory experimentation.
Note that the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art (MPEP 2164.03).
f,g) The amount of direction provided by the inventor is considered to be determined by the specification and the working examples. Inventor’s data do not demonstrate that the instant methods prevent desmoid tumors.
h) It would clearly require an extraordinary - and thus undue - amount of experimentation (clinical trials, etc.) in order to determine if, in fact, the instant methods are actually efficacious in the prevention of desmoid tumors.
Claim Rejections - 35 USC § 112(b)
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 52, 55 and 56 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term maximal is a relative term which renders the claims indefinite. The term is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Clarification is in order.
Claims 61, 66-68 and 78 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The terms avoiding and avoided are relative terms which render the claims indefinite. The terms are not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. That is, it is unclear if the terms avoiding and avoided mean that the action does not take place, or that it may take place under some circumstances but not others. Without a clear definition of the terms, the public has no way to accurately determine the metes and bounds of the claims. For purposes of examination, the terms will be interpreted as the action not taking place.
Clarification is in order.
Claim 76 is 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.
There is insufficient antecedent basis for the limitation “…the patient is a treatment naïve patient…” limitation in the claim. Claim 52, the claim from which claim 76 immediately depends, explicitly teaches that the patient has been previously treated for desmoid tumor.
Claims 57-60, 62-65, 69-75, 77 and 79-82 are also rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claims all depend, or ultimately depend, upon an indefinite claim yet do not relieve the indefiniteness. Dependent claims 57-60, 62-65, 69-75, 77 and 79-82 are also, therefore, indefinite.
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.
Claims 50, 52, 55-68, 71-73, 75 and 77-79 are rejected under 35 U.S.C. 103 as being unpatentable over PhII PF-03084014 Desmoids (NCT01981551), cited in the IDS.
In the context of a phase II trial, the reference teaches a method for treating a desmoid tumor by the oral administration of Nirogacestat at 150 mg twice a day in 21-day cycles (page 2, Background; page 2, Study Design). Patient eligibility is ≥18 years with a histologically confirmed desmoid tumor not amenable to curative resection or definitive radiation therapy that has progressed after receiving at least one line of standard treatment (page 2, Eligibility). Dose modification in the event of toxicities is explicitly taught (page 18, 3.3 DOSE MODIFICATIONS):
Grade 3 non-hematologic toxicities (other than alopecia or easily correctable
electrolyte abnormalities): withholding nirogacestat until recovery to grade ≤2, or baseline, and then administering at next lower dosage level (dose level -1: 100 mg; dose level -2: 80 mg;.
Grade 2 or higher nausea, vomiting or diarrhea: dose reduction only if not controlled by supportive measures;
Any grade of allergic reaction: discontinuation;.
Grade 3 hematologic toxicities (except any grade lymphopenia, leucopenia in the absence of neutropenia): withholding nirogacestat until recovery to grade ≤2 and then administering at next lower dosage level (dose level -1: 100 mg; dose level -2: 80 mg). If anemia, then dose reduction if there is a reduction in hemoglobin of ≥2 g/dL from baseline absent other causes e.g. nutritional deficiency.
Furthermore, the reference teaches that due to the rarity of desmoid tumors, only a limited number of clinical studies have been completed using targeted agents. However, the tyrosine kinase inhibitor imatinib, i.e. a standard treatment, shows partial response (page 7, text line 11). Nirogacestat is utilized in the form of its dibromide salt (page 44, 13.1 NIROGACESTAT (PF-03084014) (IND#119,769).
Instant independent claim 50 teaches a method of treating a desmoid tumor in a patient comprising orally administering 150 mg (free base equivalent dose) of nirogacestat or a pharmaceutically acceptable salt twice daily and reducing the dose as per the recited guidelines to 100 mg if certain toxicities (ALT, AST) are observed.
Instant independent claim 52 teaches a method of treating a desmoid tumor in a patient comprising orally administering 150 mg (free base equivalent dose) of nirogacestat or a pharmaceutically acceptable salt twice daily and reducing the dose as per the recited guidelines to 100 mg if certain toxicities (hypokalemia) are observed. Dependent claims 57-68 and 78 further define the method. Dependent claim 71 teaches the patient’s previous treatment with a tyrosine kinase inhibitor. Dependent claim 72 teaches that the patient has intrabdominal tumors. Dependent claim 73 teaches that the patient is an adult. Dependent claim 75 teaches that the patient has refractory or recurrent disease after previous treatment. Dependent claim 77 teaches that the patient is a post-menopausal woman. Dependent claim 79 teaches that the nirogacestat is the dibromide salt.
Instant independent claim 55 teaches a method of treating a desmoid tumor in a patient comprising orally administering 150 mg (free base equivalent dose) of nirogacestat or a pharmaceutically acceptable salt twice daily and reducing the dose as per the recited guidelines to 100 mg if certain toxicities (hypophosphatemia) are observed. Dependent claim 55 further defines the toxicity.
Inventor principally distinguishes over the cited prior art in that various toxicities are explicitly taught (ALT, AST, hypokalemia and hypophosphatemia). However, the instant toxicities are all encompassed by the cited prior art’s general guidance with respect to toxicities. Furthermore, the dose modifications because of these toxicities is the same as that of the instant methods. That is, absent unexpected results, the instant limitations are simply optimizations of the general guidelines of the cited art. One of ordinary skill in the art, a highly skilled individual (i.e. a clinical or laboratory physician), and with a reasonable expectation of success, would have found it obvious, before the effective filing date of the instant invention, to tailor the prior art’s guidelines to a particular patient such that resolution of observed toxicities was achieved and nirogacestat administration restarted at the lower dose. One of ordinary skill would have been motivated to perform such optimizations because it is part and parcel of the physician’s professional desire and responsibility to achieve the best outcome for each individual patient.
Clams 57-68 and 78 are included in this rejection because the limitations of these claims are drawn to active steps which are not performed; events that do not take place. That being the case, the prior art intrinsically reads on these claims, since the cited art logically recites steps which do actually take place in the method (not the literally infinite number of steps or events which do not take place in the method).
Claim 72 is included in this rejection because its limitation (intraabdominal tumors) is intrinsic to the prior art teaching.
Claim 77 is included in this rejection because its limitation (a post-menopausal woman) is intrinsic to the eligibility criteria of the prior art.
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 50, 52 and 55-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of (parent) U.S. Patent No. 11,872,211 B2, cited in the IDS. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are yet another iteration of the same overall set of limitations of the same method of treating desmoid tumor with nirogacestat in this patent thicket.
Claims 50, 52 and 55-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of (parent) U.S. Patent No. 11,951,096 B2, cited in the IDS. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are yet another iteration of the same overall set of limitations of the same method of treating desmoid tumor with nirogacestat in this patent thicket.
Claims 50, 52 and 55-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of (parent) U.S. Patent No. 12,036,207 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are yet another iteration of the same overall set of limitations of the same method of treating desmoid tumor with nirogacestat in this patent thicket.
Claims 50, 52 and 55-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of (parent) U.S. Patent No. 12,138,246 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are yet another iteration of the same overall set of limitations of the same method of treating desmoid tumor with nirogacestat in this patent thicket.
Claims 50, 52 and 55-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,872,211 B2, cited in the IDS. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are yet another iteration of the same overall set of limitations of the same method of treating desmoid tumor with nirogacestat in this patent thicket.
Claims 50, 52 and 55-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,925,619 B2, cited in the IDS. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are yet another iteration of the same overall set of limitations of the same method of treating desmoid tumor with nirogacestat in this patent thicket.
Claims 50, 52 and 55-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,925,620 B1, cited in the IDS. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are yet another iteration of the same overall set of limitations of the same method of treating desmoid tumor with nirogacestat in this patent thicket.
Claims 50, 52 and 55-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,938,116 B2, cited in the IDS. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are yet another iteration of the same overall set of limitations of the same method of treating desmoid tumor with nirogacestat in this patent thicket.
Claims 50, 52 and 55-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,951,096 B2, cited in the IDS. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are yet another iteration of the same overall set of limitations of the same method of treating desmoid tumor with nirogacestat in this patent thicket.
Claims 50, 52 and 55-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,957,662 B2, cited in the IDS. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are yet another iteration of the same overall set of limitations of the same method of treating desmoid tumor with nirogacestat in this patent thicket.
Claims 50, 52 and 55-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 12,011,434 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are yet another iteration of the same overall set of limitations of the same method of treating desmoid tumor with nirogacestat in this patent thicket.
Claims 50, 52 and 55-82 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 12,011,435 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are yet another iteration of the same overall set of limitations of the same method of treating desmoid tumor with nirogacestat in this patent thicket.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIAN J DAVIS whose telephone number is (571)272-0638. The examiner can normally be reached M-F 8:30-5:00 PM EDT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush, can be reached at 571-272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRIAN J DAVIS/Primary Examiner, Art Unit 1614 10/12/2026
