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 .
Election/Restrictions
Applicant’s election of the following species:
Compound 4, 1-(3-methoxyphenyl)-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane having the structure of:
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as the elected compound species; and
sickle cell disease as the elected disease;
are maintained.
Newly submitted claims 159 and 161-162 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species of compound and/or disease, there being no allowable generic or linking claim.
Expansion of Election of Species Requirement
A reasonable and comprehensive search of the elected species conducted by the Examiner determined that the prior art at the time of the present invention was such that it did not anticipate or render obvious the elected species; However, in light of this discovery and the claim amendments, the search is expanded to the subject matter of the subgenus of the elected compound species, i.e., the compounds having the structure of:
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and
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in addition to the elected compound species, such that it does not encompass the full scope of the claims.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on December 15, 2025, wherein claims 1-158 are cancelled; claims 159-162 are newly added. The claim amendment changes the scope of the claims by introducing new claims, such that the compound having the structure of:
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is no longer one of the compound species; and that necessitates a modification of the rejection on the record.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 159-162 are pending. Claims 159 and 161-162 are withdrawn.
Claim 160 is under examination in accordance with the elected species along with the expanded species sets forth in the Expansion of Election of Species Requirement section above.
Priority
The instant application 17/997,273 filed on October 27, 2022 is a 371 of PCT/US2021/029766 filed on April 28, 2021, which claims priority to, and the benefits of U.S. Provisional Application No.
63/127,830 filed on December 18, 2020 and U.S. Provisional Application No. 63/016,874 filed on April 28, 2020.
Action Summary
Claims 151-152, 155 and 158 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, are withdrawn in view of the claim amendments.
Claims 151-152, 155 and 158 rejected on the basis that it contains an improper Markush grouping of alternatives, are withdrawn in view of the claim amendments.
Claims 151-152 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hadari et al. (US 2017/0174699 A1), are withdrawn in view of the claim amendments.
Claims 151-152 rejected under 35 U.S.C. 103 as being unpatentable over Hadari et al. (US 2017/0174699 A1), are withdrawn in view of the claim amendments.
Claims 151-152, 155 and 158 are rejected under 35 U.S.C. 103 as being unpatentable over Hadari et al. (US 2017/0174699 A1) as applied to claims 151-152 above, and further in view of Zennadi (Int J Blood Res Disord, 2019. Vol. 6: 038), are withdrawn in view of the claim amendments.
Claims 151-152, 155 and 158 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 101 and 103 of copending Application No. 18/954,838 (reference application) in view of Vifor Pharma Group (“Annual Report 2019” [Online]. Published on March 2020), are withdrawn in view of the claim amendments submitted in the reference application.
Claim Rejections - 35 USC § 112
Claim 160 is rejected on the basis that it contains an improper Markush grouping of alternatives (newly applied as necessitated by amendment). See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
A Markush claim contains an “improper Markush grouping” if: (1) The species of the Markush group do not share a single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a "single structural similarity” when they belong to the same recognized physical or chemical class or to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent (see Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, p. 7166, left and middle columns, bridging paragraph).
The Markush grouping of compounds is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Newly submitted claim 160 recites “[a] method of treating sickle cell disease in a subject wherein the method is not prevention of sickle cell disease in a subject, comprising administering to the subject an effective amount of a compound, wherein the compound is selected from:
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…
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”. The Markush grouping of the compound species are improper, because the alternatives embraced by the Markush grouping do not share a substantial structure feature, and the alternated compound species do not share a common use that flows from the substantial structure feature.
For instance, the Markush grouping of compounds include a variety of compound species, such as
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,
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, and
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that do not share a substantial structure feature. These compound species only share the pyrimidine ring (
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) in common, and does not constitute a significant portion of the compound as a whole. According to Katoh et al. (US 4,873,248A; cited in the previous Office Action), the pyridinylpyrimidine derivatives of the formula:
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, including 2-(6-Methyl-2-pyridinyl)-4-phenylpyrimidine, are effective as fungicide (see e.g., abstract; claim 4). Even though these compound species taught by Katoh et al. share the same structure feature (pyrimidine ring), said compounds are taught to have fungicidal properties rather than treating sickle cell disease. Therefore, it is not apparent that this common structure alone (pyrimidine ring) contributes to the substantial structure feature essential for the compound to give the desired property of treating sickle cell disease.
Each of these findings demonstrate that not all members recited in the Markush groupings share a substantial structural feature and a common use that flows from the substantial structural feature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 160 is rejected under 35 U.S.C. 103 as being unpatentable over Schindler et al. (US 6,627,628 B1), in view of Stasch et al. (US 2013/0158028A1), as evidenced by CAS Registry Number 268558-14-1 (Entered STN on June 5, 2000) (newly applied as necessitated by amendment).
Schindler et al. teaches a method of activating soluble guanylate cyclase comprising administering to a patient in need thereof an effective amount of at least one compound chosen from the compounds of formula I and their physiologically tolerable salts (see e.g., claims 1 and 11). Schindler et a l. further tache a compound of Example 37, 2-(3-chlorophenyl)-4-hexamethyleneimino-6,7-dihydro-5H-cyclopenta[d]-pyrimidine hydrochloride, is an exemplary compound of formula (I) (see e.g., Col. 15, line 65-67). Please note the compound of Example 37 taught by Schindler et al. has a chemical structure of:
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, as evidenced by CAS Registry Number 268558-14-1. Schindler et al. further teaches the activation of soluble guanylate cyclase (sGC), which catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) and pyrophosphate (see e.g., Col. 18, line 7-11). Schindler et al. further teaches diseases and pathological conditions which are associated with a low cGMP level or in which an increase in the cGMP level is desired and for whose therapy and prophylaxis compounds of the formula I can be employed are, for example, cardiovascular disease such as pulmonary hypertension (see e.g., Col. 11, line 22-30). Schindler et al. further teaches the compounds of formula I,
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, in which R3 is aryl but cannot be unsubstituted phenyl; aryl is phenyl, naphthyl or heteroaryl, which can all be substituted by one or more identical or different substituents from the group consisting of, inter alia, halogen (see e.g., Col. 3, line 18 to Col. 4, line 28). Schindler et al. further teaches examples of monocyclic heterocyclic systems includes, inter alia, pyridine (see e.g., Col. 5, line 40-57). Schindler et al. further teaches a pyridyl radical can be a 2-pyridyl radical (see e.g., Col. 6, line 33-35); and the substituents in heterocycles can be situated in any desired positions, for example, in a 2-pyridyl radical in the 3-position and/or in the 4-position and/or in the 5-position and/or in the 6-position (see e.g., Col. 6, line 39-46). Schindler et al. further teaches halogen is preferably fluorine or chlorine (see e.g., Col. 7, line 5-6).
Schindler et al. does not teach sickle cell disease.
Stasch et al. teaches a method of treatment of sickle cell anemia or for the preservation of blood substitutes, comprising administering a stimulator and/or activator of soluble guanylate cyclase to a human or animal in need thereof (see e.g., claim 1; [0015]). Stasch et al. further teaches soluble guanylate cyclase (sGC) activators and stimulators can also be used for treating sickle cell anemia and associated pulmonary hypertension (see e.g., [003]). Please note the sickle cell anemia taught by Stasch et al. is a sickle cell disease.
In the present case, the difference between the method of Schindler et al. and the claimed method is that the prior art administers the compound of Example 37 that contains 3-chlorophenyl rather than 4-chloro-2-pyridyl shown below (see shaded):
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.
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the compound used in the method of Schindler et al. by replacing the 3-chlorophenyl with 4-chloro-2-pyridyl, and then incorporate a subject with sickle cell anemia as the patient to arrive at the claimed invention. One would have been motivated to do so, because Schindler et al. teaches the R3 of formula I can be a substituted phenyl or heteroaryl, such as a 2-pyridyl with a substituent in the 4-position; wherein the substituent can be a halogen that is preferably fluorine or chlorine to arrive at the compound useful for activating soluble guanylate cyclase; and Stasch et al. teaches a stimulator and/or activator of soluble guanylate cyclase can treat sickle cell anemia. One would have been further motivated to do so, because Schindler et al. teaches the compound formula I that activates soluble guanylate cyclase can treat pulmonary hypertension; and Stasch et al. teaches a stimulator and/or activator of soluble guanylate cyclase can treat pulmonary hypertension associated with sickle cell anemia. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound of Example 37 of Schindler et al., which substitutes the phenyl ring with 2-pyridyl as the heteroaryl and changes the position of chlorine to the 4 position of the 2-pyridyl, would have successfully arrive at the compound useful for activating soluble guanylate cyclase; thus, said modified would successfully treat sickle cell anemia by activating soluble guanylate cyclase, or treating pulmonary hypertension associated with sickle cell anemia in the subject.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
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.
Claim 160 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 34, 36 of U.S. Patent No. 11,746,100 B2 (reference patent), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) and Vifor Pharma Group (“Annual Report 2019” [Online]. Published on March 2020; cited in the previous Office Action) (newly applied as necessitated by amendment).
The claims of the reference patent is drawn to a method of inhibiting iron transport mediated by ferroportin in a subject, comprising administering to the subject an effective amount of a compound of Formula (I’) or a pharmaceutically acceptable salt thereof, including compound 89 having the structure of:
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; and the compound of Formula (I’):
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, wherein R3 is selected from, inter alia, hydrogen, optionally deuterated C1-C3 alkyl; R4 is
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.
The reference patent does not teach sickle cell disease and the compound.
Vifor Pharma Group teaches VIT-2763 is the first oral ferroportin inhibitor with the potential for treating disease with ineffective erythropoiesis and iron overload conditions (see e.g., p. 40, left column, 1st paragraph under “VIT-2763” section). Vifor Pharma Group further teaches VIT-2763 has shown promise in a preclinical model of sickle cell disease, a condition where formation of aberrant haemoglobin causes a variety of acute complications including painful vaso-occlusive crises, as well as severe chronic complications such as organ damage (see e.g., p. 40, left column, 1st paragraph under “VIT-2763” section). Vifor Pharma Group further teaches at the molecular level, VIT-2763 binds to ferroportin and block it to prevent excessive iron release into the blood; and ferroportin is an iron transporter that plays a key role in regulating iron uptake and distribution in the body, therefore controlling iron levels in the blood (see e.g., p. 40, right column, 1st paragraph).
Patani et al. teaches bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents (see e.g., “introduction” section on p. 3147). Patani et al. further teaches a group of bioisosteres elicit similar biological activity, and have been classified as either classical or nonclassical, wherein the classical bioisosteres are a series of replacements defined by Grimm’s Hydride Displacement Law and Erlenmeyer’s definition of isosteres:
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(see e.g., p. 3148-3149). Patani et al. further teaches isosteric divalent ring replacements obtained from Grimm’s Hydride Displacement Law resulted in retention of activity as exemplified below:
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(see e.g., p. 3158, right column, 1st paragraph), and the applicability of divalent ring-equivalent isosteres has also been demonstrate in other five- and seven-membered ring system (see e.g., p. 3158, right column, 2nd paragraph).
In the present case, the difference between the method of reference patent and the claimed method is that the prior art administers a compound that has -CH3 rather than hydrogen at R3, and has the cyclopentane ring rather than a tetrahydrofuran at the core shown below (see shaded):
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It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the compound 89 of reference patent used in the method of inhibiting iron transport mediated by ferroportin by replacing -CH3 with -H at R3, and then replacing -CH2- in the cyclopentane with -O- as taught by Patani et al., and then incorporate a subject with sickle cell disease as taught by Vifor Pharma Group to arrive at the claimed invention. One would have been motivated to do so, because Vifor Pharma Group teaches ferroportin inhibitor is useful for treating sickle cell disease by preventing excessive iron release into the blood in a subject; and the reference patent teaches R3 can be a hydrogen or optionally deuterated C1-C3 alkyl to arrive at the compound of Formula (I’); and Patani et al. teaches -CH2- and -O- are divalent ring-equivalent isosteres that can be used in five-membered ring system to result compounds in retention of activity. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound 89 of reference patent would have successfully exhibits ferroportin inhibiting effect, thus, would be similarly useful as the VIT-2763 of Vifor Pharma Group in treating sickle cell disease in a subject by preventing excessive iron release into the blood.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence of the contrary.
Response to Arguments
Applicant’s arguments filed on December 15, 2025 with respect to the rejection of claims 151-152, 155 and 158 set forth in the Non-Final Office Action mailed on July 29, 2025 have been considered but are moot because these claims are cancelled in view of the claim amendments. Newly submitted claims change the scope of the claims, and that necessitates the new ground(s) of rejection presented in this Office action for the reasons sets forth herein.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chihyi Lee whose telephone number is (571)270-0663. The examiner can normally be reached Monday - Friday 8:30 am - 5:00 pm EST.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628