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 .
Status of the Claims
Claims 1-50 are pending.
Claim Objections
Claims 7-40 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from another multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
Claims 1-6 and 41-50 are objected to because of the following informalities: Claims 1-6 and 41-50 are objected to for not reciting an article at the beginning of the claims, thus the claims are ungrammatical. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1-6 and 41-50 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant is referred to the Guidelines on Written Description published at FR 66(4) 1099-1111 (January 5, 2001) (also available at www.uspto.gov). The following passage is particularly relevant:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between structure and function, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within a genus, one must describe a sufficient number of species to reflect the variation within the genus. What constitutes a "representative number" is an inverse function of the skill and knowledge in the art. Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. In an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.
For Example MPEP 2163 states, in part,
An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”).
The instant claims are directed towards various combinations of NAPDH oxidase (NOX) inhibitors, nitric oxide synthase (NOS) inhibitors, and soluble guanylate cyclase (sGC) agonists that have therapeutic of pharmaceutical effect. The instant specification defines these terms respectively as any compound that reduces the activity of members of the NOX enzyme family, any compound that reduces the activity of members of the NOS enzyme family, and any compound that restores enzymatic activity of the soluble guanylate cyclase apoenzyme, i.e., the protein from which the heme cofactor has been removed, thereby losing its enzymatic activity. For the purpose of the invention the term “sGC inhibitor” shall also include compounds commonly categorized as “soluble guanylate cyclase stimulators” which the inventors have recently shown to be equally effective on the holoenzyme and the apoenzyme of sGC.
Claims 46, 47, 49, and 50 further require a use as a medicament or use in the prevention or treatment of brain ischemia.
With respect to the genera of substances embraced by the claims, each set of substances is claimed in terms of a function, inhibition of NOX or NOS or agonist for sGC, rather than by structure. As such the scope of the claim is enormous and embracing the subset of all existing substances that possess the claimed property, e.g. including existing substances not yet recognized as having one of the requisite functions.
As discussed in more detail below, the specification provides inadequate and insufficient examples to show possession of the full scope of the claimed genera of NOX inhibitors, NOS inhibitors, and soluble guanylate cyclase (sGC) agonists. The specification as filed does not disclose a representative number of species of the claimed genus of substances having the recited functional characteristic, nor does the specification sufficiently describe the physical characteristics of a substance that will provide the requisite inhibitory or agonist activity. This is important particularly because as time passes new indications for previously unappreciated substances or known drugs are often discovered.
The specification provides the general definitions noted above, and lists several species within each category of NOX inhibitors, NOS inhibitors, and sGC agonists. The instant specification does not provide the physical characteristics of a substance that will provide the requisite inhibitory or agonist activity.
Only 9 species of NOXi, 7 species of NOSi, and 24 species of sGC agonists are listed in the specification. The “structural characteristics” (in this case, the molecular underpinning of inhibitory or agonist response to the drug) are not discussed. Given the complexity of biological systems and medicinal chemistry in general, the disclosure of approximately 10-20 species for each category does not suffice to identify which subset all the substances in existence will possess the claimed property. In support of the examiner’s position, MPEP 2164.03 indicates that the physiological art in general is unpredictable. “A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because it is not obvious from the disclosure of one species, what other species will work.”
With respect to disclosure of a representative number of species, the level of skill of an artisan in the field of medical applications of NOX inhibitors, NOS inhibitors, and sGC agonists as well as the level of knowledge in the prior art and the predictability of the prior art must be considered. One of ordinary skill in the art in the field of the instant invention would be a collaborative team of physicians and/or pharmacologists and medicinal chemists possessing an advanced degree in biomedicine and/or a doctor of medicine degree. Thus, the level of skill is high. With regard to the state of the art, NOS inhibition will be taken as exemplary.
Dao (Handb Exp Pharmacol. 2021:264:169-204) discloses that thus far, all clinical attempts at NOS inhibition have failed even though preclinical models were positive and clinical biomarkers correlated perfectly (page 170). Practical application of NOS inhibition in the clinic may be limited as well (Dao discloses that NOS inhibition in situations of NO overproduction holds promise but likely only in acute conditions such as neurotrauma and stroke; page 170). There are three NOS enzymes, NOS1/neuronal NOS, NOS2/inducible NOS, and NOS3/endothelial NOS, with varied biological effects in health and disease (page 171-172). All three NOS enzymes generate NO by conversion of l-arginine to l-citrulline by a stoichiometric five electron oxidation utilizing molecular oxygen (O2) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) as co-substrates and several cofactors including 6R-tetrahydrobiopetrin (BH4), flavin adenine dinucleotide (FAD), and flavin mononucleotide (page 172). NOS monomer structure has two domains, the NOS heme containing amino-terminal and the carboxy-terminal domain harboring binding sites for FAD, FMN, and NADPH. Both domains are connected by linking to an calcium-binding regulatory protein, i.e., calmodulin (CaM) enhancing electron flux within the reductase domain and thus is essential for O2 to bind to NOS heme to start the NO synthesis. Ca2+-dependent CaM binding occurs in NOS1 and NOS3 following an increase in intracellular Ca2+concentrations, while NOS2 binds CaM at low intracellular Ca2+ level thus independent of elevation of intracellular Ca2+ level. There are a large number of binding and regulatory sites that could represent target motifs where a substance could potentially bind to NOS activity (page 173, 178-179). With regard to therapeutic or pharmaceutical effect, as required by the instant claims, NOS1 has been implicated in anterograde and retrograde signaling from postsynaptic neurons contributing to e.g. long-term potentiation, fear conditioning, and neurogenesis (page 174). NOS2 plays important roles in innate and adaptive immunity such as regulating T and B cells, as well as myeloid derived suppressor cells etc. (page 175). For any substance discovered to inhibit NOS, these represent just some of the potential necessary homeostatic processes requiring NOS activity that could be interrupted when an inhibitor is administered to an animal. In order for a substance to fall within the scope of “therapeutic” (instant claims 1-6) or “pharmaceutical” (instant claims 41-50), the potential for side effects due to interruption of NOS’s role during e.g. the immune response, or neurogenesis would need to be assessed. Dao discloses on page 178 that a large number of NOS inhibitors with various degrees of selectivity for NOS isoenzymes are available; However, few have reached the clinical trial stage and not all of these meet criteria for pharmaceutical developability.
In view of the foregoing, it is clear that the ability of a particular substance to inhibit one or all of the NOS enzymes would not have been a priori predictable to one of ordinary skill, and that even those compounds that had shown inhibitory activity in vitro or in animal models, may not have had properties that make it compatible with “therapeutic” or “pharmaceutical” use for several reasons.
As stated in MPEP 2163(II): If the application as filed does not disclose complete structure (or acts of a process) of the claimed invention as a whole, the examiner must determine whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. In view of the foregoing analysis, the examiner considers the preponderance of the evidence to support the position that one of ordinary skill could have a priori been able to distinguish substances having the property of NOS inhibition, NOX inhibition, or sGC activation at the time the application was filed and the required structural features for this property were not described in the specification to a sufficient degree to convey that applicant was in possession of the full scope of the claimed invention at the time the application was filed. As such, the application fails to meet the requirement for written description under 35 USC 112(a).
Claims depending from rejected claims have also been rejected because they incorporate all of the limitations of the claims from which they depend, but fail to resolve the enablement concerns outlined above.
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 1-6 and 42-47 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 1-6 and 42-45, the word "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims depending from rejected claims have also been rejected because they incorporate all of the limitations of the claims from which they depend, but fail to resolve the indefiniteness concerns outlined above.
Claim Rejections - 35 USC § 102
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 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.
Claims 1 and 2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Graus et al. (US 6,492,429; issue date: 12/10/2002).
Graus discloses a combination of apocynin (NAPDH inhibitor) and curcumin (NOS inhibitor; abstract). With regard to the preamble “Therapeutic” recited in the instant claims, this property is inherent in the substances disclosed by Graus. See MPEP 2112. A substance and its properties cannot be separated.
Claims 1 and 4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Estancial et al. (BJU Int. 2015 Oct;116(4):657-64; cited in the IDS filed 08/04/2022).
Estancial discloses a combination of the soluble guanylate cyclase activator, BAY-602770, and the NOS inhibitor, L-NAME (abstract). With regard to the preamble “Therapeutic” recited in the instant claims, this property is inherent in the substances disclosed by Estancial. See MPEP 2112. A substance and its properties cannot be separated.
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.
Claims 1, 6, 41, 46-50 are rejected under 35 U.S.C. 103 as being unpatentable over Kojda et al. (European Journal of Pharmacology 334, 181-190; publication year: 1997).
Instant claim 1 recites:
Therapeutic combination comprising: - a first therapeutic composition comprising at least one of: at least one NADPH oxidase inhibitor, at least one nitric oxide synthase inhibitor and at least one soluble guanylate cyclase agonist; - a second therapeutic composition comprising at least one of: at least one NADPH oxidase inhibitor, at least one nitric oxide synthase inhibitor and at least one soluble guanylate cyclase agonist, wherein the second therapeutic composition is different from the first therapeutic composition; and optionally - a third therapeutic composition comprising at least one of: at least one NADPH oxidase inhibitor, at least one nitric oxide synthase inhibitor and at least one soluble guanylate cyclase agonist, wherein the third therapeutic composition is different from the first therapeutic composition and is different from the second therapeutic composition; wherein optionally the first therapeutic composition, the second therapeutic composition and/or the third therapeutic composition, when present, further comprise(s) a pharmaceutically acceptable diluent and/or a pharmaceutically acceptable excipient. (Emphasis added.)
The claim therefore reads on at least two compositions comprising any one or a combination of a NOX (NAPDH oxidase) inhibitor, a NOS (nitric oxide synthase) inhibitor, and/or a sGC (soluble guanylate cyclase) agonist and requires the two compositions to be different, but the nature of the difference is not specified by the claim.
Kojda discloses a composition comprising the NOS inhibitor L-NMMA in water and a composition comprising methylene blue in water (section 2.4, page 183). These two substances are disclosed to function as NOS inhibitors (abstract). Although they are not in “a combination” per se, it would have been prima facie obvious to combine them because they were taught for the same purpose (inhibition of NOS). Please refer to MPEP 2144.06(I): "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
With regard to the preamble “[t]herapeutic” recited in the instant claims, this property is inherent in the substances disclosed by Kojda. See MPEP 2112. A substance and its properties cannot be separated.
Claims 1-6 and 48-50 are rejected under 35 U.S.C. 103 as being unpatentable over Casas et al. (Free Radical Biology and Medicine 86, pages S19-S43, abstract only; publication year: 2015).
With regard to claims 1-6 and 48, Casas discloses that both inhibiting NOX/NOS dependent oxidative stress and augmenting cGMP signaling via sGC activation are neuroprotective in stroke (ischemic stroke; abstract).
Although Casas does not disclose a therapeutic combination or a pharmaceutical composition containing each of NOX/NOS inhibitors and a sGC agonist in an example, it would have been prima facie obvious because Casas indicates this should be effective and because each category of substance is disclosed for the treatment of ischemic stroke.
With regard to claims 49 and 50, as noted above, the above composition comprising at least one each of a NOX/NOS inhibitors and a sGC agonist would be a medicament for treatment of ischemic stroke.
Claims 41-47 are rejected under 35 U.S.C. 103 as being unpatentable over Casas et al. (Free Radical Biology and Medicine 86, pages S19-S43, abstract only; publication year: 2015) as applied to claims 1-6 and 48-50 above, and further in view of Li et al. (US 20120135921; publication date: 05/31/2012).
The relevant disclosure of Casas is set forth above. Casas renders obvious combining NOX/NOS inhibitors and a sGC agonist in a pharmaceutical composition; however, Casas does not discuss including a diluent as required by instant claim 41.
Li, in the analogous art of pharmaceutical compositions (abstract, 0055), discloses that diluents are routine pharmaceutical adjuvants. This would have been merely combining prior art elements according to known methods to yield predictable results (see MPEP 2143(A)).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE PEEBLES whose telephone number is (571)272-6247. The examiner can normally be reached Monday through Friday: 9 am to 3 pm.
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, Ali Soroush can be reached at (571)272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KATHERINE PEEBLES/Primary Examiner, Art Unit 1617
Prosecution Insights