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
This office action is in response to applicant’s communication filed on 1/26/26. Claims 1, 3, 5-7 and 10-24 are pending in this application.
Claims 7, 11-12, 14-17 and 20-21 remain withdrawn.
As a result, claims 1, 3, 5, 10, 13 and 18-19 are being examined in this Office Action. Due to applicant’s amendments to the claims filed 1/26/26, the 112 rejection has been withdrawn. The examiner had an interview with the applicant on May 22, 2026 and suggested applicant insert the limitations of claim 10 into claim 1 for allowance.
Objections
Claim 10 drawn to the XRPD crystal structure of L-arginine gemfibrozil salt, the elected species, is 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.
Claim Rejections – 35 USC 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 103 (or as subject to pre-AIA 35 U.S.C. 103) is incorrect, any correction of the statutory basis 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 of this title, 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.
Claim 1, 3, 5, 13 and 18-19 are rejected under 35 U.S.C. 103(a) as being obvious over Ramirez ("Molecular architecture influences on material properties of pharmaceutical compounds", January 1, 2010 (2010-01-01), page 1, XP55806157, Retrieved from the Internet: URL: https://core.ac.uk/download/ pdf/40027947.pdf), in applicant’s IDS filed 12/7/22, in view of Gupta (Molecules, 2018, 23, 1719).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Ramirez teaches that salt formation is a strategy to improve drug solubility and that the study formed different series of amine salts of flurbiprofen, gemfibrozil, and diclofenac. (pages 1-2)
Ramirez teaches that carboxylic acids readily form salts with amine counterions and identifies gemfibrozil as one of the selected carboxylic acid drugs. Ramirez further teaches that the selected counterions included monoethanolamine, diethanolamine, and triethanolamine. (pages 23-27)
Ramirez teaches preparation of gemfibrozil amine salts by combining the drug and counterion in solvent, recovering precipitate, drying, and recrystallizing. (page 43)
Ramirez also confirms salt formation by FTIR, including transformation from carboxylic acid to carboxylate salt. (page 132)
With respect to solubility, Ramirez teaches that saturated aqueous solubility was determined for gemfibrozil and its salts. Ramirez teaches that gemfibrozil solubility was below the HPLC detection limit and that published free-gemfibrozil solubility values were 0.029 mg/ml and 0.019 mg/ml. Ramirez further teaches that saturated solubility was improved in all cases by salt formation and that counterions increased gemfibrozil aqueous solubility by over 500-fold. (pages 137-139)
(See also page 25, last two paragraphs; page 26, Fig 1.4 and first whole paragraph; page 27, see MEA and DEA structures in Fig 1.5; page 130, Fig 4.1, second to the last paragraph; page 131, 10th and 11th compounds in Table 4.1, section 4.1.1)
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
Ramirez is deficient is that it does not teach the L-arginine counterion for the gemfibrozil salt. Instead Ramirez et al. teaches the ethanolamine and diethanolamine counterion salt forms.
Ramirez is also deficient in that it does not expressly teach the claimed 100 mg/ml to 1000 mg/ml solubility range for an L-arginine gemfibrozil salt.
However, Gupta teaches arginine as a known cationic counterion for pharmaceutical salt formation. Gupta therefore provides the teaching of arginine as a known salt-forming counterion, while Ramirez provides the specific gemfibrozil salt context and the motivation to improve gemfibrozil solubility through salt formation.
More specifically, Gupta teaches that the physicochemical and biological properties of active pharmaceutical ingredients are greatly affected by their salt forms, and that the choice of a particular salt formulation is based on numerous factors including API chemistry, intended dosage form, pharmacokinetics, and pharmacodynamics. Gupta teaches that poor aqueous solubility is one of the most important reasons to employ salt formation. Gupta further teaches that different counterions can be used to address one or more shortcomings of the API. Gupta teaches a list of currently available counterions for salt formation, including arginine, diethanolamine, ethanolamine, lysine, sodium, and other cations. (pages 1-2; Table 1)
Gupta further teaches that the presence of acidic or basic functional groups is an essential requirement for salt formation, and that salt screening begins with characterization of those groups and selection of a potential counterion based on the pharmaceutical need. (page 3)
Gupta also teaches that salt formation is one of the most common methods to increase solubility and dissolution rate of weakly acidic and weakly basic drugs. (pages 5-6)
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
Therefore, it would have been obvious to one of ordinary skill in the art at the time of the invention to substitute Ramirez’s ethanolamine or diethanolamine counterion with Gupta’s arginine counterion to form an arginine gemfibrozil salt, including the L-arginine form. Ramirez teaches that gemfibrozil is a poorly soluble carboxylic acid drug, that carboxylic acids readily form salts with amine counterions, and that gemfibrozil salt formation improved aqueous solubility. Gupta teaches that arginine is a known pharmaceutical counterion and that salt formation is commonly used to improve solubility and other formulation properties.
Thus, one of ordinary skill in the art would have been motivated to select and screen arginine as a salt former for gemfibrozil because Ramirez teaches the successful formation of gemfibrozil amine salts and Gupta identifies arginine as an available cationic counterion for pharmaceutical salt formation. The substitution would have been the use of a known salt-forming counterion for its known purpose, namely improving or modifying the physicochemical properties of an acidic API.
With regard to the L-arginine limitation, it would have been obvious to use L-arginine because L-arginine is a pharmaceutically acceptable form of arginine and Gupta teaches arginine as a known pharmaceutical counterion. The selection of L-arginine would have been an obvious selection of the known and pharmaceutically useful form of arginine for forming an arginine salt of gemfibrozil.
With regard to the claimed solubility range of 100 mg/ml to 1000 mg/ml, Ramirez teaches that gemfibrozil had very poor aqueous solubility and that solubility was improved in all cases by salt formation. Gupta teaches that salt forms and counterions are selected and screened to improve solubility and other formulation properties. Thus, it would have been obvious to screen and optimize the arginine gemfibrozil salt in aqueous media to obtain a pharmaceutically useful aqueous solution.
Furthermore, the claimed solubility is considered to be a result-effective variable obtained through routine salt selection and solubility testing, or an inherent property of the obvious L-arginine gemfibrozil salt in the claimed aqueous solvent.
With regard to claims 3 and 5, it would have been obvious to test or formulate the obvious L-arginine gemfibrozil salt in water, physiological buffer, or artificial saliva because these are aqueous media relevant to oral pharmaceutical use and solubility evaluation. The particular artificial saliva composition recited in claim 5 does not patentably distinguish the claimed composition because the solubility of the obvious salt in such an aqueous medium is a property of the salt/solvent system.
With regard to claim 13, the recited process steps are treated as product-by-process limitations because the claim is directed to the gemfibrozil composition of claim 1 wherein the salt is made by specified steps. The patentability of a product-by-process claim is based on the product itself. The recited process limitations do not patentably distinguish the claimed composition absent evidence that the process imparts a structural difference to the L-arginine gemfibrozil salt.
With regard to claims 18 and 19, it would have been obvious to formulate the obvious L-arginine gemfibrozil salt as a pharmaceutical composition and oral formulation with a pharmaceutically acceptable carrier or excipient because gemfibrozil is a known pharmaceutical agent and carriers and excipients are conventional in oral pharmaceutical compositions.
Response to Arguments
Applicant’s arguments have been considered but are not persuasive for the following reasons:
The examiner acknowledges applicant’s argument that Ramirez does not teach or suggest an L-arginine gemfibrozil salt.
The examiner does not agree with applicant’s arguments. The 103 rejection does not rely on Ramirez alone. Ramirez is relied upon for teaching gemfibrozil amine salts and improved aqueous solubility by salt formation. Gupta is relied upon for teaching arginine as a known cationic counterion for pharmaceutical salt formation. Thus, the combined references would have suggested replacing Ramirez’s amine counterion with Gupta’s arginine counterion to form an arginine gemfibrozil salt.
The examiner acknowledges applicant’s argument that Ramirez does not teach a gemfibrozil salt having solubility from 100 mg/ml to 1000 mg/ml in the claimed aqueous solvent.
The examiner does not agree with applicant’s arguments. Ramirez teaches that free gemfibrozil has very poor aqueous solubility and that saturated aqueous solubility was improved in all cases by salt formation. Gupta teaches that salt forms and counterions are selected and screened to improve solubility and other formulation properties. The claimed solubility range would have been obtained by routine screening and optimization of the obvious arginine gemfibrozil salt in aqueous media, or is an inherent property of the obvious L-arginine gemfibrozil salt in the claimed aqueous solvent.
The examiner acknowledges applicant’s argument that salt selection is empirical and unpredictable, and therefore arginine could not be substituted for ethanolamine or diethanolamine with a reasonable expectation of success.
The examiner does not agree with applicant’s arguments. Obviousness does not require absolute predictability or a guarantee of success. Ramirez teaches successful gemfibrozil amine salt formation and improved solubility by salt formation. Gupta teaches arginine as a known pharmaceutical counterion and teaches salt formation to improve solubility. These teachings provide a reason to select and screen arginine for gemfibrozil salt formation with a reasonable expectation that a useful salt could be obtained.
The examiner acknowledges applicant’s declaration and argument that a person of ordinary skill would not have reasonably expected success in forming a suitable L-arginine gemfibrozil salt. The Declaration has been considered, but it does not overcome the prior art. The Declaration mainly states that salt formation may be empirical and that some salt candidates may fail. However, Ramirez already shows that gemfibrozil amine salts were successfully formed and that gemfibrozil solubility was improved by salt formation. Gupta identifies arginine as a known pharmaceutical counterion. The prior art therefore provides a reasonable basis to select and screen arginine for the same purpose.
The examiner acknowledges applicant’s argument that arginine differs from ethanolamine and diethanolamine and is not a universally optimal salt former.
The examiner does not agree with applicant’s arguments. The rejection does not require arginine to be universally optimal or identical to ethanolamine or diethanolamine. Gupta teaches arginine as a known counterion for pharmaceutical salt formation. Ramirez teaches the same acidic API, gemfibrozil, and shows that amine salt formation improves its aqueous solubility. The use of arginine would have been an obvious choice among known pharmaceutical counterions for screening and optimization.
The examiner acknowledges applicant’s argument that neither Ramirez nor Gupta teaches the L-arginine form specifically.
The examiner does not agree with applicant’s arguments. Gupta teaches arginine as a pharmaceutical counterion. It would have been obvious to use L-arginine, a pharmaceutically acceptable form of arginine, when preparing an arginine salt for pharmaceutical use. Applicant has not provided sufficient comparative evidence showing that the L-form produces an unexpected result over the closest prior art gemfibrozil amine salts.
The examiner acknowledges applicant’s argument that the selection of L-arginine was not obvious to try because multiple salt formers were available and many may fail.
The examiner does not agree with applicant’s arguments. Ramirez specifically teaches gemfibrozil amine salts and improved solubility from salt formation. Gupta identifies arginine as a known pharmaceutical counterion. A person of ordinary skill would have had a finite set of known pharmaceutical counterions to screen, including arginine, with a reasonable expectation of obtaining a useful gemfibrozil salt.
The examiner acknowledges applicant’s argument that the rejection is based on hindsight.
The examiner does not agree with applicant’s arguments because the motivation comes from the references themselves. Ramirez teaches gemfibrozil amine salts and improved solubility by salt formation. Gupta teaches arginine as a known pharmaceutical counterion and teaches salt formation to improve API properties. The combination is therefore based on the teachings of the prior art, not on Applicant’s disclosure.
The examiner acknowledges applicant’s argument that the claimed solubility is not inherent because solubility varies depending on the salt former and solvent.
The examiner does not agree with applicant’s arguments. The rejection does not assert that all gemfibrozil salts have the same solubility. Rather, once the L-arginine gemfibrozil salt is rendered obvious, the solubility of that salt in the claimed aqueous solvent is a property of the salt/solvent system. Alternatively, the claimed solubility range would have been obtained through routine screening and optimization in view of Ramirez and Gupta.
The examiner acknowledges applicant’s declaration which states that forming the L-arginine gemfibrozil salt was not routine or predictable, that other salt formers may fail, and that the claimed salt required empirical work.
These statements have been considered but are not sufficient to overcome the rejection. The declaration does not provide sufficient comparative evidence showing that the claimed L-arginine gemfibrozil salt unexpectedly outperforms the closest prior-art gemfibrozil amine salts. The declaration also does not outweigh the combined teachings of Ramirez and Gupta, which provide a reason to select and screen arginine for gemfibrozil salt formation.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jennifer Cho Sawyer whose telephone number is (571) 270 1690. The examiner can normally be reached on Monday-Friday 9 AM - 6 PM PST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Renee Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-274-1690.
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Jennifer Cho Sawyer
Patent Examiner
Art Unit: 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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