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
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A telephone call was made on 2/28/2026 in vain to clarify the issue with the Restriction Requirement 08/06/2025.
Claims 9-16 are pending, read on the elected subject matter and are examined together.
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.
Claims 9-15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Tamura US 11147791 (= WO2018101231); Osakabe, Exp Biol Mad Vol. 227(1):51-56, 2002; Kozai, Antioxidants and Redox Signalling Volume 21, Number 6, 2014; Kozikowski, J. Org. Chem. 2003, 68, 1641-1658 and Magrone, Front. Immunol., 08 June 2017.
Base claim 9: A method for activating the central nerve, comprising administering a compound in which 4 molecules of (2R,3R)-2-(3,4-dihydroxyphenyl)-3,4- dihydro-2H-chromene-3,5,7-triol are condensed by
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, , to a subject who is in need of activation of the central nerve, and adjusting the autonomic nerve activity via production of superoxide and/or hydrogen peroxide.
Tamura teaches that sympathetic nerve activation compositions which comprises polyphenols as active ingredients. The polyphenols includes the recited active ingredient elected species (claims 9, 11, 15 of ‘4 molecules’); The teaching of Tamura at column 7 lines 39-43, composition wherein tetrameric polyphenol cinnamtannin A2 falls within the range of from 5 to 500 mg, preferably from 10 to 400 mg, more preferably from 20 to 200 mg daily for adults, read on the limitations of claims 9, 11, 12, 15 with regards the active ingredient, dose and their source:
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Tamura is silent with respect to the
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(of the tetramer) or the specific disease (claim 10, relating to metabolic syndrome) and biochemical property (claims 13, 14, 16relating to production of H2O2, blocking TRP) as recited in the claims.
Specification does not disclose the specific structural formula “(‘
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’
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)” of the elected compound. See rejection under 35 USC § 112-2 in this regard. Given the criticality of the recited active ingredient, teachings with respect to known 3 tetramers are pointed out further later below in this action.
The teachings of Osakabe, Kozai, Kozikowski and Magrone are invoked to cure the deficiencies of Tamura; see further below for comparison to disclosure in the specification.
Osakabe titled “Catechins and Their Oligomers Linked by C4---t C8 Bonds Are Major Cacao Polyphenols and Protect Low-Density Lipoprotein from Oxidation In Vitro” is invoked for the deficiency of Tamura. Osakabe teaches at page 51, column B, first full paragraph line 3, oligomers linked by C4 ~ C8 bonds;, and at page 52 (Figure 1, the chemical structures of polyphenols in chocolate and cocoa) with the specific elected species (Tamura compound) clnnamtannln A2. Further Osakabe teaches at page 55 column A, the biochemical mechanism of the physiological action (in scavenging superoxide radicals) of the polyphenols. Throughout Osakabe teaches this inherent property of clnnamtannln A2 in decreasing the LDL oxidation (antioxidative activity).
Kozai titled ‘Redox Regulation of Transient Receptor Potential Channels’ reviews the significance of endogenous reactive species such as ROS and teach that TRP channels sense reactive species either indirectly through second messengers or directly via oxidative modification; at page 971 :The term ‘‘reactive oxygen species (ROS)’’ collectively describes not only the oxygen (O2) radicals, but also some nonradical derivatives of O2, and includes the superoxide anion (O2-), hydrogen peroxide (H2O2) and the hydroxyl radical (OH)” Kozai concludes at page 980, last paragraph, that ‘redox sensitivity of TRP channels is now known to mediate previously unexplained biological phenomena, and is in volved in various pathological states. A better understanding of the activation mechanisms and physiological significance of TRP channel regulation by reactive species may position TRP channels as significant pharmacological targets, which may realize the prospect of discovery of highly novel therapeutics for the management of previously untreatable diseases.
Kozikowski titled ‘Studies in Polyphenol Chemistry and Bioactivity’ is drawn to instantly elected compounds (see below the why for plurality) derived from 2-(3,4- dihydroxyphenyl)chromenylium-3,5,7-triol and nutrition, medicine, and health due to their wide range of potentially significant biological activities. According to Kozikowski, at page 1649, column B, there is a growing body of evidence suggesting that these com pounds act as potent antioxidants in vitro, ex vivo, and in vivo and may thus alter the pathophysiology of imbalances or perturbations of free radical and/or oxidatively driven processes in many diseases or directly interfere with many cellular processes. Kozikowski teaches stereochemical possibilities of multimers including the instantly elected
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tetramer (see Chart 1 at page 1642, Scheme 4 at page 1645). Kozikowski at page 1851 column B, last line onto page 1852 teaches that H2O2 to be artifactually
produced in vitro by several different polyphenolic compounds and to be responsible for causing a variety of biological activities.
Magrone at page 1, last line first paragraph, teaches that ‘following cocoa and dark chocolate ingestion, cocoa polyphenols also modulate intestinal microbiota, thus leading to the growth of bacteria that trigger a tolerogenic anti-inflammatory pathway in the host. Finally, many evidences encourage the consumption of cocoa and dark chocolate by aged people for the recovery of the neurovascular unit.
Magrone at page 8, column A, concludes that polyphenols from cocoa exert antioxidant effects, thus increasing neurological functions also preventing age-dependent damage.
Disclosure in the specification at page 23 continuation of paragraph [0062] states that compared to other polyphenols, the instant recited compound(s) exhibit astringency at lower concentrations. In this context it is interesting note that claim 12 limitation requires compound daily dose of 0.1 microgram to 1000000 microgram. Similarly, the instant compound(s) increased blood flow compared to other polyphenols (see bottom of page 25). Specification at page 27 Examples 8, 9 show increased production of H2O2 at pH 7 compared to at pH 3. Note that, real-life physiological pH is 7.4!(, which is not an assertion). Further note that specification does not disclose the chemical structure of the elected species; prior art compound Kozikowski tetramer ‘R,R compound’ has CAS Registry No. 86631-39-2 and S,S isomer of Kozikowski has CAS Registry No. 86631-38-1. Zneg noted elsewhere in this action is a cyclic tetramer. Astringency and other biological properties of polyphenols, as admitted to by the applicant, for example, TRP blocking activity (see NPL 9 at [0011] and in the citations above, are within the repertoire of one of skilled in the art. Selecting from previously known compounds using routine biological assays is within the routine practice in the pharmaceutical art. Bioassay-guided fractionation (biofractionation) is a core, iterative drug discovery process. This position taken is further predicated on the following Examination principles:
The new use for an old compound must be novel as to the use directed and unobvious.
The new use (if any) must account for the possibility that the underlying mechanism for the new therapy is the same mechanism that allows for a prior art treatment using the same compound (or its obvious variant).
The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) (Claims 1 and 6, directed to a method of effecting nonaddictive analgesia (pain reduction) in animals, were found to be anticipated by the applied prior art which disclosed the same compounds for effecting analgesia but which was silent as to addiction. The court upheld the rejection and stated that the applicants had merely found a new property of the compound and such a discovery did not constitute a new use.
As MPEP 2112 Requirements of Rejection Based on Inherency; Burden of Proof [R-10.2019], "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer."
Thus, the (elected) active ingredient, its biological property, mechanism of action of the biological property are known in the prior art. Therefore there is nothing unobvious is seen in the claims.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Schöbel, Astringency Is a Trigeminal Sensation That Involves the Activation of G Protein–Coupled Signaling by Phenolic Compounds, Chem. Senses 39: 471–487, 2014.
Osakabe, Biomolecules. 2024 Feb 17;14(2):234. doi: 10.3390/biom14020234
Sensory Nutrition and Bitterness and Astringency of Polyphenols. Post filing Review available to pick relevant prior art citations.
Fujii, Journal of Clinical Biochemistry and Nutrition (2019), 65(1), 29-33. Cinnamtannin A2, an (−)-epicatechin tetramer, was reported to have potent physiological activity.
Zeng, Crown Procyanidin Tetramer: A Procyanidin with an Unusual Cyclic Skeleton with a Potent Protective Effect against Amyloid-β-Induced Toxicity, Molecules 2019, 24, 1915.
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.
Claim 9 and dependent claims 10-15 and 16 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.
Base claim 9 and 16 drawn to a positively charged species (condensed to make the elected species) that does not have a counter ion. Further, with the cited compound being phenolic, it is unclear if phenolate salt(s) is/are intended here. The chemical structural make-up of the elected tetramer is unclear, because the term ‘condensed’ does not clarify how the monomer (triol) is linked: in linear or cyclic fashion (see below cited Note).
In re Zletz, 13 USPQ2d 1320, 1322. “An essential purpose of patent examination is to fashion claims that are precise, clear, correct and unambiguous.”
Dependent claims do not solve the problem of the base claim. As such claims 10-16 are rejected as well.
Note Kozikowski J. Org. Chem. 2003, 68, 1641-1658, tetramer compound(s) is/are linear; Zeng, Molecules 2019, 24, 1915 tetramer is cyclic.
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 9-15 and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for (the elected) compound, does not reasonably provide enablement for salt, hydrate, solvate or polymorph thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The terms salt, hydrate, solvate or polymorph are well understood umbrella terms that encompass large number of possibilities. Polymorphism in pharmaceuticals, the ability of a solid compound to exist in multiple crystalline forms, is critical because different polymorphs possess unique physical properties that directly influence drug solubility, stability, dissolution, and bioavailability. See for example, Shi, International Journal of Pharmaceutics, Volume 611, 5 January 2022, 121320) No such possibilities finds support in the specification with regards to working example, guidance or direction on how to make these things. The specification also does not reasonably provide enablement for making solvates of the claimed compounds. Note hydrate is one of many possible solvates. The specification does not enable any person skilled in the art of synthetic organic chemistry to make the invention commensurate in scope with these claims. The factors to be considered in making an enablement rejection have been summarized above. In the present case the important factors leading to a conclusion of undue experimentation are the absence of any working example of a formed solvate, the lack of predictability in the art, and the broad scope of the claims. There is no working example of any solvate or solvate formed.
Making of the tetrameric elected compound(s) is acknowledged on the basis of teachings of Kozikowski (and Zeng) discussed above. However, the compound made in Kozikowski teachings form solvates. It is clear, no hydrate or solvate is formed (see for example NMR data). The claims are drawn to solvates. These cannot be simply willed into existence Thus for examples the isolation of the compounds all involve concentration of dissolved compounds. Since the specification does not disclose any working example of how the ’condensation’ of the Tirol is done, lack of enabling disclosure for making salt, hydrate, solvate or polymorph thereof is obvious. As stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 "The specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However ... there is no evidence that such compounds exist.., the examples of the '881 patent do not produce the postulated compounds.., there is ... no evidence that such compounds even exist." The same circumstance appears to be true here. There is no evidence that solvates of these compounds actually exist; if they did, they would have formed. Hence, applicants must show that solvates can be made, or limit the claims accordingly. g) The state of the art is that is not predictable whether solvates will form or what their composition will be. In the language of the physical chemist, a solvate of organic molecule is an interstitial solid solution. This phrase is defined in the second paragraph on page 358 of West (West, Solid State Chemistry and Its Applications, john Wiley & Sons, 1984). The solvent molecule is a species introduced into the crystal and no part of the organic host molecule is left out or replaced. In the first paragraph on page 365, West (Solid-State Chemistry) says, "it is not usually possible to predict whether solid solutions will form, or if they do form what is their compositional extent". Thus, in the absence of experimentation one cannot predict if a particular solvent will solvate any particular crystal. One cannot predict the stoichiometry of the formed solvate, i.e. if one, two, or a half a molecule of solvent added per molecule of host. In the same paragraph on page 365 West (Solid State Chemistry) explains that it impossible to make meta-stable non-equilibrium solvates, further clouding what Applicants mean by the word solvate. Compared with polymorphs, there is an additional degree of freedom to solvates, which means a different solvent or even the moisture of the air that might change the stabile region of the solvate. h) The breadth of the claims includes all of the hundreds of thousands of compounds of formula (I) as well as the presently unknown list of solvents embraced by the term "solvate". Thus, the scope is broad.
The issue here is absence of disclosure with respect to predictable formation of salt, hydrate, solvate or polymorph thereof of the elected tetramer. For these reasons, one skilled in the art would be faced with undue amount of research. The specification lacks disclosure sufficient to make and use the invention commensurate with the scope of the claims. MPEP 2164.01(a) states, “A conclusion of Isaack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. ln re Wright, 999 F.2d 1557, 1562, 27 USPQ 2d 1510, 1513 (Fed. Cir. 1993).'' That conclusion is clearly justified here. Thus, undue experimentation would be required to make and use Applicants' invention.
Claims 9-15 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being treating some diseases (see claim 2 and section under 103), does not reasonably provide enablement for preventing diseases. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with the claims. Applicants are not enabled for preventing any reperfusion injuries. The only established prophylactics are vaccines not the small molecule compounds such as present here. In addition, it is presumed that “prevention” of the claimed diseases would require a method of identifying those individuals who will develop the claimed diseases before they exhibit symptoms. There is no evidence of record that would guide the skilled clinician to identify those who have the potential of becoming afflicted. The factors to be considered [in making an enablement rejection] have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art, and the breadth of the claims”, In re Rainer, 146 USPQ 218 (1965); In re Colianni, 195 USPQ 150, Ex parte Formal, 230 USPQ 546. As discussed above, preventing diseases requires identifying those patients who will acquire the disease before the disease occurs. Preventing refers to the prophylactic treatment of a subject in need thereof. This would require extensive and potentially open-ended clinical research on healthy subjects having or susceptible to for example, abdominal aortic aneurysm, atherosclerosis, artery disease, burns, cancer, cardiac arrest, cerebrovascular disease, cerebral edema secondary to stroke, chronic obstructive pulmonary disease, congestive heart disease, constriction after percutaneous transluminal coronary angioplasty, coronary disease, diabetes, hypertension, mechanical trauma resulting from crush injury or surgery. migraine, myocardial infarction, peripheral vascular disease, pulmonary vascular disease, reperfusion after cardiac surgery, reperfusion after stroke, retinal vascular disease, stroke and surgical tissue reperfusion injury. There is no working example of such a preventive procedure in man or animal in the specification. Extension of ex vivo or in vitro data to real life use of the elected compound for preventing any and all the diseases (see claim 12) does not find support in the instant specification. The claims rejected are drawn to clinical use of medicine and are therefore physiological in nature. The state of the art is that no general procedure is art-recognized for determining which patients generally will become afflicted with the disease before the fact. The artisan using Applicants invention would be a Board Certified physician in treating diseases with an MD degree and several years of experience. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of cancer generally. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIZAL S CHANDRAKUMAR whose telephone number is (571)272-6202. The examiner can normally be reached M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625