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, 89, 93, 94, 98, 101, 105-108, and 115-119 are pending, wherein Claim 115-119 are newly added. Claims 116, 117 and 119 are withdrawn. Therefore, Claims 88, 89, 93, 94, 98, 101 and 105-108, 115 and 118 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 was made in the reply filed on 11/28/2025.
In response to Applicant’s amendment requiring administration of both sGC stimulator and sGC activator, the search was broadened to the extent necessary to consider the newly aged sGCa limitation. The Examiner’s search and examination have been extended to include cinaciguat as the sGCa species in combination with the previously elected sGCs species. This limited expansion of the search and examination does not constitute an examination of, or withdrawal of the election requirement as to, the remaining nonelected sGCa species. The other sGCa species encompassed by the pending claims remain nonelected and are withdrawn from further consideration.
Claims 116, 117 and 119 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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, 115 and 118 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
Maintained
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 Rejections - 35 USC § 112
New rejections, necessitated by amendment
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.
Claim 115 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.
Regarding claims 115, the term “preferably” renderd 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 Rejections - 35 USC § 103
New rejections, necessitated by amendment
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.
A. Claims 88, 89, 93, 94, 98, 101 and 105-108, and 115 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 to said patient
an effective dose of a soluble guanylate cyclase (sGC) stimulator compound (sGCs), and
an effective dose of a soluble guanylate cyclase activator compound (sGCa),
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 1) teach an effective dose of a soluble guanylate cyclase activator compound or 2) 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.
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. Stasch teaches that sGCs and sGC activators (sGCa) target different redox states of sGC. sGC stimulators act on reduced, heme-containing sGC and synergize with NO, whereas sGC activators preferentially and effectively activate oxidized or heme-free sGC. See p. 2; see also Figure 1 and accompanying text. sGC activators also protect sGC from degradation. See Figure 1 text. An example of an sGC activator is cinaciguat. See p. 2 and ‘Pulmonary hypertension’ section starting at p. 6. 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 and an sGCa such as cinaciguat because Ghofrani teaches a method of treating PAH by administering riociguat (an sGC stimulator) and Stasch teaches PAH is associated with altered sGC redox states, including the presence of heme-free sGC, while still retaining heme-containing sGC, and further teaches that sGCs target reduced, heme-containing sGC whereas sGCa preferentially target oxidized or heme-free sGC. Therefore, the POSA would have sought to additionally administer an sGC activator such as cinaciguat to target the oxidized or heme-free sGC (apo-sGC) population described by Stasch, while riociguat targets the reduced, heme-containing sGC population with a reasonable expectation of increasing sGC-cGMP signaling and effectively treating PAH.
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 selected from, inter alia, riociguat. Riociguat is taught by Ghofrani as outlined above. This also meets the limitation of Claim 94.
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.
Response to arguments
Applicant's arguments have been fully considered but have not been found to be persuasive.
Applicant argues that Stach teaches sGC stimulators (sGCs) and sGC activators (sGCa) as having different mechanisms and utility in different disease groups and therefore provides no reason to administer the agents together. These arguments do not address the rejection as presently made. Ghofrani teaches treating PAH with riociguat, an sGCs, while Stasch teaches that pulmonary hypertension is associated with altered sGC redox states, including increased heme-free sGC, and that sGCs act on reduced heme-containing sGC whereas sGCa preferentially activate oxidized or heme-free sGC. Thus, the different activities relied upon by Applicant provide, rather than negate, the reason for the combination. Stasch’s statement that the two classes “may thus have utility in different groups of diseases” does not criticize, discredit, or otherwise discourage the claimed combination and therefore does not teach away.
Regarding Applicant’s additional arguments regarding discovery that sGCs directly activates apo-sGC and the post-filing data allegedly demonstrating additive, synergistic, or unexpectedly enhanced effects similarly do not overcome the rejection. The claims under examination are not commensurate in scope with the Applicant’s alleged unexpected results. Applicant is also reminded that the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." See MPEP § 716.02(b).
B. Claim 118 is 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), as applied to Claims 88, 89, 93, 94, 98, 101 and 105-108, and 115 above, taken further in view of PFIZER(WO 2005/011727).
Claimed invention
Claim 118 limits claim 88, wherein the sGCa is provided as a unit dose comprising 0.5 mg - 500 mg of the one or more sGCa.
Prior art
Ghofrani and Stasch teaches the method as discussed above, including administration of riociguat and the activator cinaciguat, but does not expressly teach the claimed unit dose of 0.5-500mg cinaciguat.
PFIZERteaches formulations for treating cardiovascular or metabolic disorder containing sGC activators can be expected to be in the range of from 5 to 500mg of soluble guanylate cyclase activator. A preferred dose is in the range 10 to 200mg (e.g. 10, 25, 50, 100 and 200mg). See abstract, p. 12, last par.; see also p. 13.
The POSA would have found it obvious to administer the cinaciguat of Stach at a dose within the range taught by PFIZERbecause the reference teaches that such doses are suitable therapeutic doses for sGC activators administered to human subjects. The reference amounts fall squarely within the clamed range of 0.1-500mg.
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 CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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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
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