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
Election of Species and Status of the Claims
Applicant’s election without traverse of Example 1 as the single specific non-covalent dimer cation in the response filed on December 21st 2025 is acknowledged. Claims 1-20 are pending. Claims 4 and 6 are withdrawn from further consideration as being directed towards nonelected species until a generic claim has been found allowable. Claims 1-3, 5, and 7-20 are examined on their merits.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The Information Disclosure Statement filed on September 27th 2023 is in compliance with the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of references cited from the IDS is included with this Office Action.
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 17-20 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.
Claims 17-20 are indefinite for reciting a method without an intended subject. Claim 17 recites “a method of antioxidation comprising administering the cation of claim 1.” Claim 17 appears to be intended as a ‘method of treatment’ claim (as demonstrated with its dependent claims 18-20). However, no subject receiving administration of the cation is recited in any of claims 17-20.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 18 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claim recites a method of reducing or reversing oxidative stress in human or animal cells comprising administering the cation of claim 1 to said cells. This judicial exception is not integrated into a practical application because only contact of the cells with the cation (i.e. a natural phenomenon) and the result of said contact is recited. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because only the natural phenomenon and the result of said natural phenomenon (the inhibition, reduction, or reversal of oxidative stress) is recited.
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 1-3, 5, 7-11, 13, and 17-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhao (Zhao et al., Dimeric Histidine as a Novel Free Radical Scavenger Alleviates Non-Alcoholic Liver Injury. Antioxidants. 2021; 10(10):1529).
Claims 1-3, 5, and 7-8 are directed towards applicant’s elected species of:
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.
Applicant’s elected species is a dimer of two histidine molecules, wherein one of the molecules is positively charged on the imidazole group (as is well-known in the art to occur on the imidazole of histidine), and said charged group forms a hydrogen bond with the carboxyl end of the other histidine molecule.
Zhao teaches the histidine dimer,
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(Zhao, pg. 5).
Zhao illustrates a hydrogen bond between the two imidazole groups on the histidines. However, this interaction is not the only instance of hydrogen bonding that would occur on these molecules. In a solution of water (as would be found in any animal cell), the hydrogen bonds described above would not be present in a stable form, but would be breaking and reforming, both with the present water molecules and the histidine molecules. Therefore, in any aqueous solution wherein multiple histidine molecules are present, several hydrogen-bonding patterns would necessarily be present. While one of those interaction patterns is the imidazole-imidazole interaction described by Zhao, another is the imidazole-carboxylic acid interaction shown below:
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.
That is to say, the hydrogen-bonding patterns would be considered an inherent property of the histidine dimer, and in a solution of said histidine dimers, the imidazole-carboxylic acid interaction would necessarily occur. Thus, Zhao’s histidine dimer is equivalent to applicant’s elected species and is anticipatory of claims 1-3, 5, and 7-8.
Claims 9-10 are directed towards the chloride salt of the cation of claim 1. Zhao teaches a preparation process of the above histidine dimer, described below:
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[Zhao, pg. 2]
Zhao’s process involves the preparation of the histidine dimer cation via reaction of multiple histidine molecules with NH-4Cl, followed by drying and purification. In the reaction vessel, the NH4Cl would act as NH4+ and Cl--, with the NH4+ serving as a proton source (providing the charge on the cation) and the Cl- forming an ionic bond with the histidine dimer cation product. The dried end product would necessarily not be merely the cation, but a neutral salt of the histidine dimer cation and the Cl- anion. Therefore, Zhao describes the chloride salt of the histidine dimer and is anticipatory of claims 9-10.
Claim 11 is directed towards a method of preparing the above histidine dimer cation comprising, contacting the first histidine with an acid, contacting the resulting acid salt with a salt, adding the second histidine, and adding a base. The above synthesis method described by Zhao describes the addition of a solution of NH4Cl to L-histidine. In said solution, the NH4 behaves as a weak acid, the NH4Cl serves as the added salt, and the water behaves as a weak base. Thus, the reaction described by Zhao is equivalent to that described in claim 11, wherein:
The histidine reactant is contacted with the acidic ammonium chloride
The second histidine reactant is contacted with the above reaction
The above reaction is contacted with the basic water
Zhao thus describes the preparation method of claim 11 and anticipates claim 11.
Claim 13 is directed towards the method of claim 11 wherein the reaction temperature is between 0 and 70 degrees Celsius in every step. Zhao’s method occurs at room temperature (Zhao, pg. 2), and Zhao thereby anticipates claim 13.
Claims 17-20 are directed towards the treatment of nonalcoholic fatty liver disease (NAFLD) via administration of the cation of claim 1. Zhao teaches the treatment of NAFLD via administration of the above histidine dimer (Zhao, pg. 13), anticipating claims 17-20.
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.
Claims 12, and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao (Zhao et al., Dimeric Histidine as a Novel Free Radical Scavenger Alleviates Non-Alcoholic Liver Injury. Antioxidants. 2021; 10(10):1529).
Claim 12 is directed towards the method of claim 11 wherein the acid is selected from HCl, HBr, and HI, and the added salt is an ammonium salt. For the teachings of Zhao as they relate to claim 11 see the above 102 rejection for claim 11. Regarding the added salt, Zhao teaches ammonium chloride (Zhao, pg. 2). Regarding the use of an acid such as HCl instead of NH4Cl, as the reaction described by Zhao is an ordinary acid-base reaction (see the above 102 rejections over Zhao), one of ordinary skill in the art would have a reasonable expectation of success in substituting another acid in place of the ammonium chloride. As hydrochloric acid is one of the most common acids used in such acid-base reactions, one of ordinary skill in the art would find the substitution of HCl for the acid, and thus claim 12, prima facie obvious.
Claim 14 is directed towards the method of claim 11 wherein
The ratio of histidine to acid is between 1:2 and 1:10
The ratio of the histidine acid salt to salt is 1:2 to 1:10
The ratio of histidine cation to histidine is 1:1 to 1:2
For the teachings of Zhao as they relate to claim 11 see the above 102 rejection for claim 11. Regarding the ratio of histidine to acid and the ratio of histidine to salt, Zhao teaches a ratio of 1:4 of histidine to NH4Cl, wherein NH4Cl serves as both the acid and the salt in the reaction. Zhao does not explicitly describe the ratio of histidine acid-salt to NH4Cl, but one of ordinary skill in the art performing such reaction would recognize that the concentrations would change throughout the reaction, gradually shifting the histidine:acid ratio down, histidine acid salt: salt ratio down (starting from a zero point for the acid salt) and the cation: histidine ratio upward (starting from a zero point for the cation). One of ordinary skill in the art would therefore reasonably expect each of the three ratio conditions would therefore be expected to be met over the course of the reaction, and claim 14 is prima facie obvious.
Claim 15 requires that, in the method of claim 11, the pH is less than or equal to 6. For the teachings of Zhao as they relate to claim 11 see the above 102 rejection for claim 11. Zhao does not explicitly teach the pH of the reaction solution. However, one of ordinary skill in the art would recognize the reaction performed as an ordinary acid-base reaction wherein the ammonium ion donates a proton to the histidine. Such a reaction would generally occur in a solution considered ‘acidic,’ that is, a solution wherein the pH is less than 7. Any further lowering of the pH to initiate a proton transfer to the histidine would therefore be considered a matter of routine optimization, and claim 15 is thereby prima facie obvious.
Claim 16 is directed towards the method of claim 11 wherein the base is selected from ammonia water, NaOH, KOH, or triethanolamine, and the adding of the base adjusts the pH to be greater than or equal to 8. For the teachings of Zhao as they relate to claim 11 see the above 102 rejection for claim 11. Regarding the identity of the base, the water in Zhao’s synthesis is used to wash away any excess ammonium ions (i.e. to neutralize the acid) to purify the histidine dimer product. As the reaction described by Zhao is an ordinary acid-base reaction (see the above 102 rejections over Zhao), one of ordinary skill in the art would have a reasonable expectation of success in substituting another base in place of the water in order to remove the excess acid from the product. As sodium hydroxide is one of the most common acids used in such acid-base reactions, one of ordinary skill in the art would find the substitution of NaOH for the base obvious. Regarding raising the pH above 8, such a reaction would generally occur in a solution considered ‘basic,’ that is, a solution wherein the pH is greater than 7. Any further raising of the pH to remove excess acid from the product would therefore be considered a matter of routine optimization, and claim 16 is thereby prima facie obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Anthony Seitz whose telephone number is (703)756-4657. The examiner can normally be reached 7:30 AM ET - 5:00 PM ET M-F.
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/A.J.S./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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