DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/07/2026 has been entered.
Response to Amendment
Applicant’s response of 07/07/2026 has been received and entered into the application file. Claims 1, 3-7, and 10-20 are pending in this application.
Applicant’s amendments to the Specification and claims have overcome 102 rejections, previously set forth in the Final Office Action mailed 04/07/2026.
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.
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.
Claims 1, 3-7, and 10-20 are rejected under 35 U.S.C. 103 as being unpatentable over Yam et al. (WO 2022/197948 A1, Priority: 03/18/2021), Flores-Pulido et al. (Synthesis and use of copper histidinate in children with Menkes disease in Mexico, Gac Med Mex, 2018), and Alam et al. (US 5036060, 1991).
Yam discloses copper histidinate compositions and uses thereof. The disclosure shows that treatment of Menkes disease patients with copper histidinate increases survival of the patients (Abstract). Yam discloses a pharmaceutical composition of lyophilized copper histidinate and a pharmaceutically acceptable carrier ([0011]). The lyophilized copper histidinate is reconstituted with saline; a concentration of about 2.9 mg/mL ([0011]). The formulation is stable for greater than two months and preferably at least about 18 months ([0012]). The lyophilized powder upon reconstitution was clear blue solution ([0135], Table 6). The lyophilized powder product is reconstituted with normal saline for subcutaneous injections ([0093]). Yam discloses that a vial label for reconstitution of the lyophilized copper histidinate in saline and subcutaneous administration to a subject with Menkes disease states a dose of 0.5 mL per administration (claim 13). Along with stability, one of ordinary skill in the art would routinely experiment with lyophilized products to avoid any unnecessary lumping, aggregating, and/or lyophilization defects; especially for a pharmaceutical composition potentially used for humans.
Yam does not explicitly mention sodium hydroxide as pH adjusting agent.
Flores-Pulido discloses preparation method of copper histidinate; copper chloride and L-histidine were dissolved in sodium chloride; the solution’s pH was adjusted to 7.38-7.40 using sodium hydroxide solution (pg 176).
Above references do not explicitly mention sodium chloride as a lyoprotectant.
Alam discloses a mannitol-free lyophilized formulation of cyclophosphamide; sodium chloride is present as an excipient (abstract). Alam discloses that a suitable amount of sodium chloride can be added to the cyclophosphamide solution; the vessel may then be filled to the desired final volume with water. The pre-lyophilization solution should be sterilized prior to lyophilization. The lyophilization process is well-known to those skilled in the art and should be readily adaptable for use (col 3, lines 1-35). From analyzing the data, it is clear that the cyclophosphamide lyophilizate obtained through the use of sodium chloride meets the requisite standards for being a commercial product. The results are dramatic and surprising, especially when they are compared to the results shown with respect to the long-term storage stability testing (col 6, lines 48-60).
Yam discloses a lyophilized pharmaceutical composition comprising copper histidinate and pharmaceutically acceptable excipients. Flores-Pulido discloses that sodium hydroxide is routinely used to adjust the pH. Alam discloses that sodium chloride can be used as a lyoprotectant for improved stability of lyophilized compositions. Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above to arrive at a lyophilized pharmaceutical composition comprising copper histidinate, sodium hydroxide, and sodium chloride. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 3, one of ordinary skill in the art would consider the use of sodium chloride as a lyoprotectant as taught by Alam.
Regarding claims 4-5, the use of sodium hydroxide as a pH adjusting agent is discussed above.
Regarding claim 6, the dose of copper histidinate is taught by Yam.
Regarding claim 7, Alam discloses that the amount of sodium chloride employed is usually from about 0.1 to about 3 parts by weight per 100 parts of water, in the pre-lyophilization product (col 3, lines 1-10). One of ordinary skill in the art would routinely experiment with different concentrations of sodium chloride in a pre-lyophilization product.
Regarding claim 8, one of ordinary skill in the art would expect a lyophilized product to be available in powder or cake..
Regarding claim 10, Alam discloses that the color/clarity of cyclophosphamide/NaCl at 4 degrees Celsius was clear/colorless after 3 months as well as consistent assay values (Table V). Additionally, Yam discloses that the formulation is stable for 18 months when stored at about 2 to 8 degrees Celsius ([0059]).
Regarding claim 11, one of ordinary skill in the art would routinely monitor for any impurities for a pharmaceutical composition administered via injections. And it would have been obvious to monitor in this case as well.
Regarding claim 12, one of ordinary skill in the art would routinely experiment with different mixing vehicles for an injectable such as sodium chloride, or sterile water as taught by Alam.
Regarding claims 13-14, one of ordinary skill in the art would routinely test for stability for lyophilized products. Yam discloses the formulation being stable for 18 months at about -10 to -20 degrees Celsius, 2 to 8 degrees Celsius, or 15 to 30 degrees Celsius ([0059]). Likewise, one of ordinary skill would text for stability at different temperatures.
Regarding claim 15, the pH is discussed above.
Regarding claims 16-17, 2.9 mg/mL of copper histidinate and a dose volume are discussed above.
Regarding claim 19, Yam discloses a stable lyophilized formulation of copper histidinate, wherein the formulation is made by lyophilizing an aqueous solution comprising L-histidine and Copper II Chloride Dihydrate, adjusted to a pH of about 7.35 in an aqueous solution, followed by lyophilization of solution ([0059]). Alam also discloses common lyophilization processes – an active ingredient (cyclophosphamide) sodium chloride and water were mixed before lyophilization. One of ordinary skill in the art would immediately envisage that a lyophilization process involves an active ingredient such as copper chloride dihydrate, L-histidine, sodium chloride, and a pH adjusting agent. The resulting solution or mixture would then be lyophilized. This process is not new and one of ordinary skill in the art would routinely practice it.
Regarding claim 20, Yam discloses that lyophilized copper histidinate compositions are used for Menkes disease (claims 13-15).
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Yam et al. (WO 2022/197948 A1, Priority: 03/18/2021), Flores-Pulido et al. (Synthesis and use of copper histidinate in children with Menkes disease in Mexico, Gac Med Mex, 2018), and Alam et al. (US 5036060, 1991) as applied to claims 1, 3-7, and 10-20 above, and further in view of Wang (Tolerability of hypertonic injectables, International Journal of Pharmaceutics, 2015).
Wang teaches that injectable drug products are ideally developed as isotonic solutions (Abstract). The main goal in formulation development for injectable products are to control the product solubility, to extend/optimize product storage stability, and to maximize both local and systemic tolerability upon injection (Introduction). Based on the literature data, it is clear that the osmolality of a drug product should be controlled ideally at a level around 300 +/- 30 mOsm/kg (Section 4.2). Wang discloses many hypertonicity-induced effects such as enhanced site irritation/pain and possible tissue damage (Table 1).
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to control the osmolality value of an injectable copper histidinate product to avoid hypertonicity-induced effects such as enhanced site irritation/pain and possible tissue damage. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Response to Arguments
Applicant’s arguments filed 07/07/2026 have been fully considered but they are not persuasive.
On pages 6-7 of remarks, applicant argues that the prior knowledge teaches one of ordinary skill in the art away from the claimed invention. Basak discloses that “the presence of sodium chloride causes aggregations during lyophilization resulting in a turbid solution when reconstituted with sterile water”. The Basak reference discloses that “copper-histidine was formulated in freeze-dried form”. Basak does not mention what copper salts are mixed with L-Histidine to create the copper histidinate compound. In the instant specification, the applicants mixed copper chloride dihydrate, L-histidine in water for injection. Furthermore, applicants have specific ingredients in specific quantity as shown in Example 1. Claim 1 of instant application is a broad claim of a lyophilized pharmaceutical composition comprising copper histidinate with any and all excipients. Claim 1 simply is not commensurate in scope with the data presented in Example 1. What did the applicants do differently than the combined teachings of prior art? Is it a specific quantity of copper and/or histidine mixed together? Is it a specific quantity of sodium chloride and/or sodium hydroxide? The Examiner cannot determine why their invention separates from prior arts. Paragraph [0057] of Yam discusses that “pharmaceutically acceptable carrier” includes many materials that could be considered “excipients”. One of ordinary skill in the art would immediately envisage that a composition comprising copper histidinate and one or more pharmaceutically acceptable excipients can be lyophilized.
On page 8 of remarks, applicant argues that there is no reasonable expectation of success. Alam relates to cyclophosphamide, a completely different compound from copper histidinate. However, Alam was relied upon to teach that sodium chloride is routinely considered as a lyoprotectant for various pharmaceutical compositions. Applicant further argues unexpected results. As mentioned above, claim 1 is not commensurate in scope with how the unexpected results are presented in the instant specification. Example 1 comprises a composition comprising copper chloride dihydrate, L-histidine, sodium chloride, sodium hydroxide and sterile water. None of these ingredients are listed in claim 1. The composition of Example 1 was carefully mixed and the pH level was adjusted to 7-7.5 using sodium hydroxide. Why was this crucial step omitted from claim 1? Can the composition be formed without aggregates at any pH levels? The unexpectedness cannot be determined as currently claimed.
On page 9 of remarks, the declaration provided by the inventor argues the same points as already discussed above. The Examiner encourages the applicants to amend claim 1 to commensurate in scope with the data presented.
Conclusion
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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