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 .
Detailed Action
Response to Remarks
The arguments submitted in the remarks of 06/24/2026 are persuasive and the rejections made in the previous obvious action have been withdrawn.
However, on further consideration, the claims are rejected under new grounds.
Status of Claims
Claims 53-79 are currently pending.
Claims 63, 67, 72-73, and 75 are withdrawn.
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 53-62, 64-66, 68-71, 74, and 79 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 a method of inhibiting a thiol isomerase via administration of theaflavin 3-gallate, theaflavin 3,3’-digallate, and pentagalloyl-glucose, does not reasonably provide enablement for inhibiting a thiol isomerase via administration of gallic acid. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The following Wands factors have been considered: (A) The breadth of the claims, (B) The nature of the invention, (C) The state of the prior art, (D) The level of one of ordinary skill, (E) The level of predictability in the art, (F) The amount of direction provided by the inventor, (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Breadth of the claims
Claim 53 is drawn to a method of inhibiting a thiol isomerase in a subject in need thereof, comprising administering a therapeutically effected amount of a galloylated polyphenol selected from theaflavin 3-gallate, theaflavin 3,3’-digallate, and pentagalloyl-glucose, and gallic acid.
Nature of the Invention
The invention is a method of inhibiting an enzyme. Therapeutic efficacy is not explicitly claimed in claim 1. The instant specification connects inhibition of the thiol isomerases to anti-thrombotic and/or anti-platelet aggregation.
State of the art
A search of the art connects protein disulfide isomerase (PDI) to anti-thrombotic effects. Gaspar (frontiers in pharmacology, vol. 10, art. 1678, 2020) in its introduction, para. 1 states “Cardiovascular diseases are the leading cause of death worldwide, a scenario where thrombosis and its associated outcomes account for one in four deaths [citations omitted]. Platelets play a key role in arterial thrombosis, due to platelet aggregation triggered by multiple agonists, such as adenosine diphosphate (ADP), thrombin, and collagen. These signaling pathways will inevitably culminate in the activation of the platelet surface integrin αIIbβ3, which becomes activated after the isomerization of critical disulfide bonds on its extracellular β domain. This process is thought to be mediated by protein disulfide isomerase (PDIA1, herein referred to as PDI) and sibling proteins. Therefore, PDI has been proposed as a new target to treat and prevent thrombotic diseases.”
Therefore, one of ordinary skill in the art would at least see that inhibition of PDI could be purposed for anti-thrombotic efforts. This is affirmed in Flaumenhaft (WO2022104153, of the record).
Flaumenhaft is drawn to “compounds of Formula I…and methods of using the compound of Formula (I) for treating viral infections and inhibiting thrombosis are also provided (abstract). Throughout the reference, flavonoids are discussed. Starting on p. 18, Flaumenhaft discusses flavonoids and starting on p. 52, Examples 1, Flaumenhaft teaches the structures of flavones, flavanones, and flavenes (classes of flavonoids). Methods of using the above compounds are contemplated starting on p. 34, l. 32 which includes “a method of inhibiting protein disulfide isomerase (PDI) in a cell. Anti-thrombotic activity is shown in Flaumenhaft, p. 96, example 6. Considering these teaching, one of ordinary skill in the art could view potential to use flavonoids as a class of compounds effective in inhibiting PDI. However, the only compound tested within Flaumenhaft is pinocembrin 7-O-(3’’-galloyl-4’’, 6’’-(S)-hexahydroxydi[phenoyl)-β-D-glucose (PGHG), structure shown in Fig. 13 and below.
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Where the instant compounds differ is both in general structure and galloylation. Theaflavin is listed in Flaumenhaft (p. 13, l. 31). However, neither galloylated theaflavin or pentagalloyl glucose are listed. The structure of theaflavin and glucose are shown below.
Theaflavin
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Considering the difference in structures and degree of galloylation, one of ordinary skill would need to test the theaflavin and then test the degree of galloylation.
However, the art indicates that gallic acid’s ability to inhibit platelet aggregation is neglible or high concentrations are required. Gaspar on p. 5, sec. Myricetin Was More Potent Than Gallic Acid in Inhibiting Platelet Aggregation states “Gallic acid was unable to inhibit platelet aggregation, except at the higher concentration used (300 μM) in TRAP-6 activated platelets.” It is not clear whether these platelets are associated to PDI or any of the other thiol isomerases claimed.
Guidance and Working Examples
In addition to the discussion regarding gallic acid above, the instant specification on p. 47, sec. Galloylated polyphenols inhibit thiol isomerases states “Neither pinocembrin, gallic acid nor glucose showed substantial activity against thiol isomerases.”
Theaflavin 3-gallate, theaflavin 3,3’-digallate, and pentagalloyl glucose results showing inhibition are shown in figures 14B and 15A-B.
Quantity of Experimentation and Predictability
Considering the above, one of ordinary skill cannot predictably inhibit PDI or other thiol isomerases using gallic acid. The art and instant disclosure indicate that gallic acid requires high concentrations of inhibiting platelet aggregation induced by a separate pathway.
As claims 54-62, 64-66, 68-71, 74, and 79 are dependent on claim 53, they are also rejected.
Allowable subject matter
Claim 76-78 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims allowed.
Allowable subject matter indicated.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUISALBERTO GONZALEZ whose telephone number is (571)272-1154. The examiner can normally be reached M-F 8:30-5:30.
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/LUISALBERTO GONZALEZ/Examiner, Art Unit 1624
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