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 .
Application and Claims Status
In the amendment as filed on 12/20/2024, applicants have amended claims 30, 49, 56, 63, 68, 69, 128-131, 135, and 137-141; cancelled claims 2, 4, 6-29, 31-48, 50-55, 57-62, 64-67, 70-127, 132-134, and 142-178; and added no new claims. Therefore, claims 1, 3, 5, 30, 49, 56, 63, 68-69, 128-131, and 135-141 are currently pending and claims 1, 3, 5, 30, 49, 56, 63, 68-69, 128-131, and 135-141 are presently under examination.
Priority
The instant application is a 35 U.S.C. § 371 national stage filing of No. PCT/US2022/052411, filed December 9, 2022, which claims the benefit of U.S. Provisional Application No. 63/288,377, filed December 10, 2021, United States Provisional Application No. 63/421,524, filed November 1, 2022, and United States Provisional Application No. 63/429,376, filed December 1, 2022. Applicant is awarded the priority date to earliest provisional, 63/288,377, filed December 10, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 9/19/2024 is in compliance with the provisions of 37 CFR 1.97. All references have been considered except where marked with a strikethrough. A signed copy of Form 1449 is included with this Office Action.
Specification
Acknowledgement is made of the drawings received June 6, 2024.
The drawings are objected to because:
In FIG. 3, the text is blurry and illegible. In FIG. 4, the label of the y-axis is illegible. In FIG. 9, the graphs and labeling are blurry and illegible. In FIG. 10, the x-axes are illegible. As recited in 37 CFR 1.84:
(l) Character of lines, numbers, and letters. All drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined. The weight of all lines and letters must be heavy enough to permit adequate reproduction. This requirement applies to all lines however fine, to shading, and to lines representing cut surfaces in sectional views. Lines and strokes of different thicknesses may be used in the same drawing where different thicknesses have a different meaning.
FIG. 4 is also objected to because it is unclear what the y-axis is meant to indicate (i.e. ‘0001’, ‘0004’). If the y-axis is the assigned reference number to a patient, it should be indicated as such.
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 Objections
Claim 49 is objected to because of the following informality: for consistency with claims 1 and 3, the semicolon in “...seven days; followed thereafter…” should be replaced with a comma. Appropriate correction is required.
Claim 130 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 129. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). In the instant case, claim 130 is drawn to the method of claim 3, wherein Compound I is administered as a pharmaceutical composition. The method of claim 3 comprises Compound I, or a pharmaceutical salt thereof, and thus claim 130 is drawn to Compound I, or a pharmaceutical salt thereof.
Claim 137 is objected to because of the following informalities: the clause “as provide by the administration of Compound I” should read “as provided by the administration of Compound I” (emphasis added). Appropriate correction is required.
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 1 and 137-141 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.
Claims 1, 137-139, and 141 are rejected as vague and indefinite for recitation of the phrase “provide about 25% to about 60% hemoglobin occupancy” or “reaches about 25% to about 60%”. It is not possible to fully determine the range of doses that would lead to the result to be achieved claimed and for which protection is sought. This has the effect that a person skilled in the art cannot clearly decide which doses are to be covered by the claims and which are not. Therefore, the metes and bounds are unclear. Claim 141, which depends on claim 139, and does not resolve the ambiguity, is also rejected.
Claims 140-141 are rejected as vague because it is not clear if the blood concentration levels of “about 50 µg/mL to about 800 µg/mL” (claim 140) or “about 300 µg/mL to about 475 µg/mL” (claim 141) after administration of Compound I are levels reached after the administration of the first dose or second dose of Compound I.
Claim Rejections – 35 USC § 112(a)
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.
Scope of Enablement - Prevention
Claims 1, 3, 5, 30, 49, 56, 63, 68-69, 128-131 and 135-141 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AlA), first paragraph, because the specification, while being enabling for treatment, does not reasonably provide enablement for prevention. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The following Wands factors have been considered if not explicitly discussed: (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.
The term “treatment” or “treating” is defined in the specification (pages 6-7, para [0047]) and said definition also embraces prevention, writing: “…preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition” (emphasis added).
It is presumed “prevention” of the claimed condition would require a method of identifying those individuals who will develop the claimed condition before they exhibit symptoms. The current state of the art is that that full scope of diseases claimed within instant claims is not preventable or curable.
There is no evidence in the prior art that the instant composition would be usable as a preventative method, particularly for preventing diseases such as sickle cell. “Preventing” connotes an absolute absence of a condition which cannot reasonably be achieved with regard to infections, with few exceptions (such as vaccines to prevent the development of pathogen-borne illnesses). In addition, there is no definitive method by which to determine whether a patient will develop a particular condition and, thus, be in need of preventive therapy. This is distinguished from preventing the relapse or recurrence of certain conditions, in which case an objective basis may exist to identify patients at risk of disease or infection, and could reasonably be construed as treatment. Prior to the initial onset or occurrence, however, even if a patient can be identified as having known risk factors for a condition, there is no certainty that the patient would in fact develop the condition. Further, the failure of a disease, infection, or condition to develop cannot reliably be attributed to the claimed active agent(s). The non-development of a condition such as diseases like sickle cell may be due to other factors such as lifestyle. In this sense, in the context of preventing a disease, the level of unpredictability is extremely high.
The factors to be considered in making an enablement rejection were summarized above. 1) Preventing diseases requires identifying those patients who will acquire the condition before the symptoms occur. This would require extensive and potentially open-ended clinical research on healthy subjects. 2) There is no working example of such a preventive procedure in man or animal in the specification. 4) The claims rejected are drawn to clinical pharmacology and are therefore physiological in nature. 5) The state of the art is that no general procedure is art-recognized for determining which patients generally will develop sickle cell disease before the fact. 6) The artisan using Applicants invention would be a Board Certified physician. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of sickle cell disease Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable for any agent to be able to prevent sickle cell disease. 7) It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved" and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). 8) The claims broadly read on all patients, not just those undergoing therapy for the claimed conditions.
As claims 5, 30, 49, 56, 63, 68-69, 128-131 and 135-141 depend upon claims 1 and 3 and do not resolve the rejection, they are also rejected.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 3, 5, 30, 49, 56, 63, 129-131 and 137-141 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Brown et al. (“GBT021601, a Next Generation HbS Polymerization Inhibitor: Results of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Adults Living with Sickle Cell Disease and Healthy Volunteers”, published November 5, 2021)(hereinafter, ‘Brown’).
Brown discloses a first-in-human (FIH) phase 1 study of GBT021601, an oral, small molecule next-generation HbS polymerization inhibitor for the treatment of sickle cell disease. GBT021601, also referred to as osivelotor, is the same compound of the instant claims, as evidenced by PubChem.
Regarding claims 1, 137-139, and 141: Brown reports, “The SCD [sickle cell disease] patient study tests a single dose (100 mg) followed by multiple ascending doses of the study drug in the same patients to reach a % Hb occupancy of > 20-30% over 7 weeks”. Thus, Brown teaches dosing that provides “about 25% to about 60% hemoglobin occupancy”.
Brown teaches a period of 7 weeks, which implies a first dose is given “for one, two, three, four, five, six, or seven days,” (as recited in instant claims 1 and 3) and dosing (of a second dose) is continued beyond said time frames for up to 7 weeks. Thus, the reference embraces the dosing regimen of instant claims.
Furthermore, claims 1, 137-139, and 141 are drawn to properties based on the administration of the claimed compound (e.g. the % hemoglobin occupancy), which are inherently present. Said properties would also be present if administering the cited species in Brown.
Regarding claims 3, 5, 30, 49, 56, 63, 129-131, and 140: Brown reports, “The SCD [sickle cell disease] patient study tests a single dose (100 mg) followed by multiple ascending doses of the study drug in the same patients to reach a % Hb occupancy of > 20-30% over 7 weeks”. Additionally, Brown teaches, “Doses administered to HV [healthy volunteer] cohorts ranged from 50 mg to 2200 mg”, which embraces the range of instant claim 3.
Each and every required element of the claims are taught, and the claims are anticipated
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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) 1, 3, 5, 30, 49, 56, 63, 68-69, 128-131 and 135-141 are rejected under 35 U.S.C. 103 as being unpatentable over Brown and Parent et al. (US 2022/0363674 A1, published November 17, 2022, effectively filed May 14, 2021)(hereinafter, ‘Parent’).
The previous 102 rejection is incorporated herein.
Regarding claims 135-136: Parent discloses a crystalline form of the instant Compound I (reference claim 1), a pharmaceutical composition comprising the crystalline form of Compound I (reference claim 22), as well as a pharmaceutical composition comprising a crystalline form of Compound I and another therapeutic agent (reference claim 26). Parent further specifies (page 9, para [0156] a short list of other therapeutic agents in the pharmaceutical composition, which includes “hydroxyurea, L-glutamine, crizanlizumab, or deferiprone” (emphasis added). Furthermore, the prior art teaches a method for treating sickle cell in a subject in need thereof, comprising administering Compound I (reference claim 30).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, at the
time before the effective filing date of the claimed invention, to practice the method of treating taught by Brown and combine it with an additional therapeutic agent taught by Parent. Both prior art references are directed to the same compound for the same use, and Parent teaches the additional therapeutic agent in a pharmaceutical composition.
Regarding claims 68-69 and 128: The instant claims are drawn to an administration frequency of once daily (QD) or twice daily (BID). Brown reports daily dosing of GBT021601. In this instance, modifying concentrations or quantities (result effective variables) would be obvious based on routine optimization (In re Aller), unless there is evidence to the contrary. Dosage and treatment regimen are result-effective variables, i.e. a variable that achieves a recognized result. Therefore, the determination of the optimum or workable administration frequency would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the criticality of the claimed administration frequency, the determination of the optimum administration frequency given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."). Accordingly, claims 68-69 and 128 are rejected.
Thus, said claims are rendered obvious.
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 1, 3, 5, 30, 49, 56, 63, 68-69, 128-131 and 135-141 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of copending Application No. 19/490,232 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Both sets of claims encompass a method of treating sickle cell disease by administering a first and second dose of Compound I, wherein the first dose and the second dose provide about 25% to 60% hemoglobin occupancy (instant claim 1), or the first dose is about 200 mg per day to about 1600 mg per day and the second dose is about 25 mg per day to about 500 mg per day (instant claim 3). The only difference is reference clams 1 and 3 specify administering Compound I for eight or more days. This limitation is necessarily included in instant claim 1, which has a first day for one to seven days, followed by a second dose, which could necessarily be on the eighth day and so on.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
All claims are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUKE ALAN BORALSKY whose telephone number is (571)272-9746. The examiner can normally be reached Monday - Friday 7:30 am - 5:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey H Murray can be reached at 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.A.B./Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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