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 Status
Claims 88-114 are pending. Claims 90-92, 95-97, 99, 100, 102-104, are 109-114 are withdrawn. Therefore, Claims 88, 89, 93, 94, 98, 101 and 105-108 are examined on the merits.
Election/Restrictions
Applicant’s election without traverse of Group I (method of treating CVD) and a soluble guanylate cyclase (sGCs) stimulator compound as the only ingredient administered in the reply filed on 11/28/2025 is acknowledged.
Claims 90-92, 95-97, 99, 100, 102-104, are 109-114 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions (Claims 90 and 109-114) and species (Claims 91, 92, 95-97, 99,, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/28/2025.
Therefore, Claims 88, 89, 93, 94, 98, 101 and 105-108 are examined on the merits.
Priority
This application is a 371 of PCT/NL2021/050111 filed 02/18/2021 and claims priority to
NL2024965 filed 02/21/2020.
Specification
Furthermore, the following guidelines illustrate the preferred layout for the specification of a utility application. These guidelines are suggested for the applicant’s use.
Arrangement of the Specification
As provided in 37 CFR 1.77(b), the specification of a utility application should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase “Not Applicable” should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A READ-ONLY OPTICAL DISC, AS A TEXT FILE OR AN XML FILE VIA THE PATENT ELECTRONIC SYSTEM.
(f) STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR.
(g) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art including information disclosed under 37 CFR 1.97 and 1.98.
(h) BRIEF SUMMARY OF THE INVENTION.
(i) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(j) DETAILED DESCRIPTION OF THE INVENTION.
(k) CLAIM OR CLAIMS (commencing on a separate sheet).
(l) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(m) SEQUENCE LISTING. (See MPEP § 2422.03 and 37 CFR 1.821 - 1.825). A “Sequence Listing” is required on paper if the application discloses a nucleotide or amino acid sequence as defined in 37 CFR 1.821(a) and if the required “Sequence Listing” is not submitted as an electronic document either on read-only optical disc or as a text file via the patent electronic system.
Claim Objections
Claims 88, 93, 94, 98, 101 107 and 108 are objected to because of the following informalities:
Claim 88: The term “wherein the patient has a cardiovascular disease related to the presence of apo-sGC” should be “wherein the cardiovascular disease is related to the presence of apo-sGC”.
Claim 93: The term “is/are” should be “is”.
Claim 94: The term “is/are” should be “is”.
Claim 98: The terms “0,05”, “0,1”, “0,2”, and “0,4” should be “0.05”, “0.1”, “0.2”, and “0.4”, respectively.
Claim 101: The terms “0,1”, “2,5”, “0,05”, and “0,1” should be “0.1”, “2.5”, “0.05”, “0.1”, respectively.
Claim 107: The term “relating” should be “related”.
Claim 108: The term “augment(s)” and “stimulate(s)” should be “augments” and “stimulates”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 89, 93, 98, and 101 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 89, 98 and 101, the terms "such as" and “preferably” render the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 93 refers to tables in the specification that contain a list of sGC agents. It is indefinite to reference Tables 3 and 4. The content in the tables is required to be placed into the claims. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." See MPEP § 2173.05(s). Because the current invention can be defined in words, the limitations from the tables are required to be incorporated into the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 88, 89, 93, 94, 98, 101 and 105-108 are rejected under 35 U.S.C. 103 as being unpatentable over Ghofrani et al. (N Engl J Med (July 25, 2013); 369(4)) in view of Stasch et al. (“Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease.” Circulation. 2011 May 24;123(20):2263-73. doi: 10.1161/CIRCULATIONAHA.110.981738. PMID: 21606405; PMCID: PMC3103045).
Claimed invention
Independent Claim 88 is drawn to a method for:
treating cardiovascular disease (CVD) in a patient in need thereof, comprising the step of
administering an effective dose of a soluble guanylate cyclase (sGC) stimulator compound (sGCs) to said patient,
wherein the cardiovascular disease is related to the presence of apo-sGC (i.e., heme-free sGC).
Prior art
Ghofrani teaches riociguat, a soluble guanylate cyclase (sGC) stimulator, has been shown in a phase 2 trial to be beneficial in the treatment of pulmonary arterial hypertension (PAH), a cardiovascular disease (CVD). See Ghofrani, abstract. Riociguat directly stimulates soluble guanylate cyclase (sGC) independently of nitric oxide availability. In several phase 1 and 2 clinical studies, riociguat improved hemodynamic variables and exercise capacity in patients with PAH. See Ghofrani, p. 331, 2nd par.
Ghofrani does not expressly characterize PAH as being related to the presence of apo-sGC, nor do they discuss alterations in sGC redox state or heme loss as part of the disease pathology.
However, Stasch teaches that CVDs, including PAH, are associated with dysregulation of the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway as a result of oxidative stress, which leads to oxidation of the sGC heme and, under sustained conditions, loss of the heme moiety, thereby increasing levels of oxidized and heme-free sGC (apo-sGC) in CVD. Stasch, p. 2. Stasch further teaches such disease states retain heme-containing sGC capable of pharmacological activation, even though NO responsiveness is reduced. Stasch, p. 2. Stasch teaches that sGC stimulators act on heme-containing sGC, increase cGMP production independently of nitric oxide (NO) and sensitizes sGC to low levels of endogenous NO. See Stasch, p. 2. In regard to pulmonary hypertension, Stasch describes the total sGC expression is increased due to increase in heme-free sGC (apo-sGC), while NO-sensitive sGC signaling is reduced, indicating the continued presence of heme-containing sGC in the disease state. Stasch, Fig. 2 legend at p. 18. Thus, Stasch describes certain CVDs as being associated with the presence of apo-sGC as a consequence of changes in sGC due to oxidative stress.
A person of ordinary skill in the art (POSA) would have found it obvious to treat PAH characterized as related to apo-sGC by administering an effective amount of riociguat because Ghofrani teaches a method of treating PAH by administering riociguat (an sGC stimulator) and Stasch teaches PAH is associated with altered sGC redox state including the presence of apo-sGC while still retaining heme-containing sGC. The POSA would have had a reasonably expectation of effective treatment of PAH related to apo-sGC with riociguat because PAH is described as having a mix of both heme-absent sGC (i.e., apo-sGC) and heme-containing sGC and sGC stimulators are described to act on the heme-containing sGC.
Claim 89 limits claim 88, wherein the patient suffers from, inter alia, pulmonary arterial hypertension. Both references teach PAH as indicated in the rejection above.
Claim 93 limits claim 88, wherein the sGCs is any one or more of the sGCs listed in Table 3. Claim 94 limits claim 88, wherein the sGCs is any one or more of, inter alia, riociguat (BAY 63-2521). Riociguat is taught by Ghofrani as outlined above.
Claim 98 limits claim 88, wherein the sGCs is provided as a unit dose comprising 0.05-100 mg of the sGCs. Claim 101 limits claim 88, wherein the sGCs is provided as a unit dose comprising 0.1-5.0 mg riociguat. Ghofrani teaches patients received unit doses at amounts of 1.5 mg and 2.5 mg three times daily. See Ghofrani, abstract. Thus, teaching unit doses of 1.5 mg and 2.5 mg which meet the claimed range of unit doses.
Claim 105 limits claim 88, wherein the method treats cyclic 3’,5’-guanosine monophosphate (cGMP) deficiency in the patient. Claim 106 limits claim 105, wherein the treatment comprises stimulation of cGMP formation in the patient in need of said treatment. Claim 108 limits claim 105, wherein the sGCs augments stimulation of heme containing sGC and augments stimulation of sGC by NO. Stasch teaches that sGC stimulators act on heme-containing sGC, increase cGMP production independently of nitric oxide (NO) and sensitizes sGC to low levels of endogenous NO. See Stasch, p. 2.
Claim 107 limits claim 105, wherein the patient suffers from a medical condition relating to sGC dysfunction and/or relating to cGMP deficiency. Both references teach PAH, a medical condition relating to sGC dysfunction and relating to cGMP deficiency.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/ Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622