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 without traverse of Group I, encompassed by claims 1-5, drawn to compositions of phosphodiesterase 5 (PDE5) inhibitor and a glucocorticoid receptor (GR) antagonist, in the reply filed on 03/06/2026 is acknowledged.
Applicant further elected the following species, without traverse, as described below:
A single PDE5 inhibitor: Applicant elected mirodenafil as the PDE5 inhibitor.
A single GR antagonist: Applicant elected CORT-108297 as the GR antagonist.
A single neurodegenerative disease: Applicant elected dementia as the neurodegenerative disease.
Applicant has not pointed to any errors in the Examiner' s analysis of the classification of the different inventions. The requirement is still deemed proper and is therefore made FINAL.
Claims 6-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/06/2026.
Application and Claims Status
Claims 1-16 were pending. Claims 6-16 are withdrawn. Therefore, claims 1-5 are currently under examination.
Priority
The instant application is a continuation-in-part application of PCT/KR2022/005818, filed April 22, 2022, which claims the benefit of Korean Patent Application No. 10-2021-0052930, filed April 23, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 10/23/2023 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 – Disclosure
The disclosure is objected to because of the following informality:
On page 1, line 10, Applicant abbreviates phosphodiesterase 5 inhibitor as “(PED5)”, when it should appropriately be abbreviated as PDE5. Appropriate correction is required.
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any of the errors of which applicant may become aware of in the specification.
Specification - Drawings
Acknowledgement is made of the drawings received 10/23/2023.
The drawings are objected to because:
Currently, in FIG. 1 and FIG. 2, the y-axis label, x-axis label, and x-axis numbers 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.
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
Claims 3 and 4 are objected to because of the following informality: there is an extra space between “…flunisolide; and at least one species…” that should be removed. Appropriate correction is required.
Claims 3 and 5 are objected for their use of non-standard Markush claim language. Markush claims are commonly formatted as “wherein R is independently selected from the group consisting of A, B, and C” or “wherein R is A, B, C, or D”. In claim 3, as an example, applicant recites “…at least one species selected from a group consisting of pharmaceutically acceptable salts, solvates, or hydrates thereof” (emphasis added). Proper Markush claim language could optionally recite “……at least one species selected from a group consisting of pharmaceutically acceptable salts, solvates, and hydrates thereof” or “…at least one species is a pharmaceutically acceptable salt, solvate, or hydrate thereof”. Relevant guidance can be found in the MPEP § 2173.05(h), titled “Alternative Limitations,” which deals with claims that list alternatives.
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 2-4 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.
Claim 2 is rejected as vague for its recitation of the term “a mixture”. Claim 2 is attempting to narrow the scope PDE5 inhibitor species of claim 1, as well as “a mixture thereof”. Is Applicant claiming a mix of the species, as in mirodenafil mixed with sildenafil? Examiner recommends amending the claim to read “…and a combination thereof” (emphasis added) instead.
Claims 3-4 are rejected as vague and indefinite for their recitation of “…and at least one species
selected from a group consisting of pharmaceutically acceptable salts, solvates, or hydrates thereof.” The current claim is interpreted such that the composition contains a GR antagonist that “is CORT-108297, prednisolone, dexamethasone, mifepristone, ciclesonide, budesonide, cortisone, flunisolide” and a GR antagonist that is “at least one species selected from a group consisting of pharmaceutically acceptable salts, solvates, or hydrates thereof”. Does the composition contain both a single species and a separate species of pharmaceutically acceptable salts, solvates, or hydrates? Appropriate correction is required.
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(s) 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (US 2015/0297599 A1, published October 22, 2015)(hereinafter, ‘Kim’, corresponding to US 9,750,743 B2) and clinical trial NCT04601038 (first submitted October 19, 2020, first published October 23, 2020)(hereinafter ‘NCT04601038’).
Regarding PDE5 component of claims 1-5, and mirodenafil of claims 4-5, Kim discloses a pharmaceutical composition comprising PDE5 (e.g. mirodenafil) for inhibiting brain neuron apoptosis and treating neuronal degenerative disease associated with brain neuron apoptosis (e.g. dementia, Alzheimer's dementia etc.) (See abstract, [0049], [0055], claims 14-23).
Kim discloses neuronal degenerative disease that could be prevented or treated by the phosphodiesterase 5 inhibitor, e.g. dementia, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis, wherein the dementia is AIDS-induced dementia, Lewy body dementia, frontotemporal dementia, multi-infarct dementia, semantic dementia, Alzheimer's dementia, and vascular dementia, etc. (See [0064], claim 17).
Kim does not disclose combining mirodenafil or any PDE5 inhibitor with a glucocorticoid receptor (GR) antagonist (e.g. CORT-108297).
Regarding GR antagonist of claim 1-5, and CORT-108297 of claims 3-4, NCT04601038 teaches a Phase II clinical trial of administration of the GR antagonist, CORT108297 in 26 individuals with cognitive impairment due to Alzheimer’s disease and in 26 cognitively normal individuals with an increased risk of Alzheimer’s disease due to family history, genetics, and/or subjective memory complaints. Alzheimer’s disease is a severe form of dementia.
It has been held that combinations of two or more compositions each of which is taught by the prior art to be useful for the same purpose in order to form a third composition which is to be used for the very same purpose is prima facie obvious. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As the court explained in Crockett, the idea of combining them flows logically from having been individually taught in prior art.
That is, generally, if it is known to use A, and known to use B for the same purpose, then it is obvious to use both A and B, In re Susi, 169 USPQ 423, 426; In re Kerkhoven, 205 USPQ 1069.
Regarding the supposed “more than additive and synergistic” effect taught in the instant specification (e.g. Example 4, page 9-10, and Table 1 therein), the Office has stated: “A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue.” In re Corkill, 711 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating “synergism”). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).
In the instant case, Applicant has not demonstrated a “more than additive and synergistic” effect of Aβ reduction upon treatment with both a PDE5 inhibitor and GR antagonist. For example, Table 1 (page 9-10) shows the average reduction rate of Aβ42 upon treatment with mirodenafil (AR1001)—the PDE5 inhibitor component—alone with a value of 1.77. Table 1 further shows the average reduction rate of CORT108297—the GR antagonist component—alone at various concentrations: for instance, at 2.4 µM of CORT108297, average reduction rate of Aβ42 is 17.91. The additive value of these two individual reduction rates, that is Aβ42 reduction rate upon treatment with mirodenafil plus the Aβ42 reduction rate upon treatment with 2.4 µM of CORT108297, is 19.68. Table 1 teaches that the Aβ42 reduction rate upon combined treatment of both mirodenafil and 2.4 µM of CORT108297 is 20.00. This increase of 0.32 units amounts to a 1.6% increase in supposed Aβ42 reduction. This can not possibly amount to a significant, practical advantage and is of statistical insignificance. This analysis can be performed at all of the taught concentrations of CORT108297 used alone and in combination with mirodenafil to arrive at the same conclusion. Furthermore, at the lowest and highest reported concentrations (0.1 and 3.0 µM, respectively) of CORT102897 administration, Applicants actually observed a worse outcome—that is, the combined treatment was worse than additive effects of the treatments alone.
Altogether, it would have been obvious to one of the ordinary skill in the art before the effective filing date of instantly claimed invention to combine the PDE5 inhibitor (e.g. mirodenafil) taught by Kim with GR antagonist CORT108297 taught by NCT04601038 and arrive at the instant claimed invention with reasonable expectation of success. At the time the invention was made, it was known that both the PDE5 inhibitor (e.g. mirodenafil) taught by Kim and the GR antagonist (e.g. CORT108297) taught by NCT04601038 could be used for treating Alzheimer /dementia. A skilled artisan would be motivated to combine PDE5 inhibitor (e.g. mirodenafil) taught by Kim with CORT108297 because both teachings are directed to treatment for neurological disease (e.g. Alzheimer/dementia). A skilled artisan would expect the pharmaceutical composition comprising PDE5 inhibitor (e.g. mirodenafil) and CORT108297 might provide an alternative synergistic combination therapy for treating Alzheimer’s dementia.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of treating Alzheimer and dementia. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of 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.
Claims 1-5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over at least claim 6 of copending Application No. 19/151,272 (hereinafter, ‘272’) in view of Schatzberg et al. (US Patent No 6,150,349, published November 21, 2000)(hereinafter, Schatzberg’).
Instant claims 1-5 are drawn to a composition comprising a PDE5 inhibitor (e.g. mirodenafil) and a GR antagonist (e.g. mifepristone). Reference claim 1 of ‘272 is drawn to a composition comprising a PDE5 inhibitor (e.g. mirodenafil) and reference claim 6 is drawn to the composition of claim 1, further comprising an antidepressant, an anxiolytic, an alpha-1 blocker, or a combination thereof. The reference does not teach that a GR antagonist can be used as an antidepressant.
Schatzberg teaches a composition comprising a GR antagonist, which inhibits the binding of cortisol to its receptors, to be used in ameliorating psychotic major depression. Schatzberg teaches mifepristone as a potent GR antagonist to be used. (See abstract; col 2, lines 9-20; col 4, lines 64-67; col 7, lines 49-60; claims 1-13). Altogether, Schatzberg teaches a composition comprising a GR antagonist (e.g. mifepristone) as an antidepressant.
In view of the teachings of Schatzberg, reference claim 6 of ‘272 teaches a composition comprising a PDE5 inhibitor and further comprising an antidepressant. Schatzberg teaches GR antagonists (e.g. mifepristone) are known antidepressants. The teachings of Schatzberg render the claimed GR antagonist species as obvious when combined with the genus of antidepressants. Thus, reference claim 6 of ‘272 teaches a composition comprising a PDE5 inhibitor (e.g. mirodenafil) and a GR antagonist (e.g. mifepristone).
This is a provisional nonstatutory double patenting rejection.
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 am.
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/L.A.B./Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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