DETAILED ACTION
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 .1
Status of the Claims
Claims 1 and 3-15 are pending in this application. Claims 1, 3-9 and 14-15 are under examination. Claims 6-7 and 10-13 are withdrawn.
The examined claims are directed to the species elected without traverse on July 14, 2025, glycolic acid, a calcium channel blocker, and oral administration.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 15/776,817, filed on 05/17/2018.
Terminal Disclaimer
The terminal disclaimer filed on Nov 26 2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of 18018935 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Response to Arguments
Applicant’s arguments, filed Nov 26 2025, with respect to the rejection of claims 1-5, 8-9, and 14-15 for lack of written description under 35 USC 112(a) have been fully considered and are persuasive. Claim 1 was amended to recite “said ester of glycolic acid is cleaved in vivo to release glycolic acid” so as to overcome the written description rejection. Support for this amendment is found in paragraph 30, noting “In some embodiments the ester is intended to enable cleavage of the ester in vivo,
thereby releasing GA as the active component.” The rejection of claims 1-5, 8-9, and 14-15 has been withdrawn.
Applicant’s arguments, filed Nov 26 2025, with respect to the rejection of claims 1, 3, 4, 5, 8, 9, 14 and 15 as being obvious over Tang in view of Perricone & Dinardo and Kloner, in further view of the ‘799 patent have been considered but are not persuasive. Claims 1, 3, 4, 5, 8, 9, 14 and 15 remain rejected as detailed below.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1, 3, 4, 8, 9, 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Tang et al. "The Cardioprotective Effects of Citric Acid and L-Malic Acid on Myocardial lschemia/Reperfusion Injury," Evidence-Based Complementary and
Alternative Medicine Volume 2013, Article ID 820695, 11 page, in view of Perricone & Dinardo, Dermatologic Surgery Volume 22, Issue 5 May 1996 Pages 435-437 and Kloner, Nifedipine in Ischemic Heart Disease Circulation Volume 92, Issue 5, 1 September 1995; Pages 1074-1078. Tang and, Perricone & Dinardo, are cited on page 2 of the July 27, 2022 IDS.
Claim 1 is directed to a pharmaceutical composition comprising glycolic acid, pharmaceutically acceptable salt or ester thereof and a further ischemia-reducing compound, such as the elected species of calcium channel blocker, wherein said ester of glycolic acid is cleaved in vivo to release glycolic acid.
Glycolic acid is known in the art to belong to a class of compounds with similar properties known as alpha-hydroxy acids (AHA).
Regarding claim 1 and use of ischemia reducing compounds, it is noted the specification discloses the need to protect a subject from ischemic injury, inclusive of cerebral and cardiovascular ischemia (stroke, heart attack, myocardial ischemia/ infarction, reperfusion injury) etc. The basis to do so is established by Tang, where it teaches the use of AHAs, such as citric acid and malic acid, to treat myocardial ischemia/reperfusion injury:
Inflammatory responses and platelet aggregation have been implicated in
myocardial ischemia/reperfusion injury [26]. Within minutes after reperfusion,
inflammatory cascade is triggered and copious amounts of proinflammatory
cytokines such as TNF-a, IL-1/J, IL-6, and IL-8 are produced and released [27].
These proinflammatory cytokines (particularly TNF-a), as important factors in
cardiac dysfunction, activate neutrophils and endothelial cells and aggravate
myocardial ischemia/reperfusion injury [28, 29]. Platelets play a critical role in the process of myocardial ischemia/reperfusion injury. After reperfusion, platelets
are immediately activated and increased, and platelet aggregability will aggravate
myocardial ischemia/reperfusion injury in tum, which may be related to
endothelial dysfunction and platelet-derived p-selectin, and so forth [30]. The
results showed that [alpha hydroxy acids] both citric acid and L-malic acid decreased TNF-α level and inhibited platelet aggregation on myocardial ischemia/reperfusion injury. These data in vivo provided direct evidence that organic acids protected ischemia myocardium may be partly due to inhibition of inflammation and platelet aggregation.
See Tang, page 9, within column 1 (emphasis added).
And although Tang teaches that the anti-inflammatory effects of certain AHAs
can have therapeutic and/or protective effects of certain types of ischemic injuries, he
does not explicitly identify glycolic acid.
However, one of ordinary skill in the art would recognize glycolic acid to be an art-accepted equivalent to malic acid and citric acid because each of these AHAs are part of common chemical grouping having comparable anti-inflammatory activities, and have a reasonable expectation that glycolic acid could
be used to treat ischemic injuries.
Similar to Tang demonstrating the anti-inflammatory effects of AHAs citric acid
and L-malic acid in a subject, Perricone teaches that in two studies, another AHA,
glycolic acid was and demonstrated to have an anti-inflammatory property upon the subject's skin cells exposed to UVB radiation, see abstract. Thus, the combination of Tang and Perricone provide a skilled artisan the rationale to look towards using glycolic acid similarly to citric acid and L-malic acid, because each of these AHAs are part of common chemical grouping with comparable anti-inflammatory activity.
While Tang and Perricone combined, teach the treatment of myocardial ischemia with glycolic acid, due to the anti-inflammatory properties of AHAs generally, they do not teach a combination composition further comprising an ischemia-reducing compound, such as the elected species of a calcium channel blocker.
To address this, Kloner teaches the elected species, calcium channel blocker, nifedipine, is used to treat ischemic heart disease, including the myocardial ischemic condition, myocardial infarction. See title and page 1, 2nd full paragraph.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings Tang using anti-inflammatory AHAs to treat myocardial ischemia, to choose glycolic acid as the AHA and administer with the calcium channel blocker, nifedipine, as taught by Perricone,
The PHOSITA would have had a reasonable expectation of success because the use of calcium channel blockers is known in the art to treat myocardial ischemia, and accordingly, as Tang and Perricone teach the use of glycolic acid to treat myocardial ischemia. It would be obvious to a PHOSITA to combine these two myocardial ischemia treating compounds into a single composition. See MPEP 2144.05 I. (Combining Equivalents Known for the Same Purpose).
Regarding claims 3 and 4, requiring oral/liquid formulations, it would be obvious to administer a composition comprising AHAs such as glycolic acid orally, where Tang teaches its subjects were administered the AHAs citric and L-malic acid orally, where these test rats were compared with control/sham/placebo groups orally administered 0.9% saline solution. See Rat Group 5 under Section 2.3 Drug Pretreatment and Myocardial Ischemia/Reperfusion Protocols. Further, see Footnote 43 of Kloner noting orally administered calcium channel blocker, nifedipine. Based on the combined teachings of Tang and Kloner, a PHOSITA would routinely optimize a liquid orally administered formulation comprising glycolic acid and nifedipine.
Regarding claims 8 and 9 requiring the ischemia-reducing compound be a calcium channel blocker (i.e., nifedipine), Kloner teaches nifedipine to treat myocardial ischemia. See above
Regarding claims 14-15 requiring at least one of a calcium channel blocker, in a liquid form configured for oral administration, as discussed above, the teachings of Tang, Perricone and Kloner teach these limitations, oral liquid formulations comprising glycolic acid and the calcium channel blocker nifedipine.
Claims 1, 3-5, 8, 9, 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Tang et al. "The Cardioprotective Effects of Citric Acid and L-Malic Acid on Myocardial lschemia/Reperfusion Injury," Evidence-Based Complementary and
Alternative Medicine Volume 2013, Article ID 820695, 11 page, in view of Perricone & Dinardo, Dermatologic Surgery Volume 22, Issue 5 May 1996 Pages 435-437 and Kloner, Nifedipine in Ischemic Heart Disease Circulation Volume 92, Issue 5, 1 September 1995; Pages 1074-1078, in further view of US Pat 5,516,799 A.
The ‘799 patent is recited on page 2 of the of the IDS filed July 27, 2022.
While the combination of Tang, Perricone and Kloner render claims 1, 3, 4, 8, 9 and 14-15 obvious, they do not necessarily teach the species of claim 5.
Regarding instant claim 5 wherein glycolic acid or a pharmaceutically acceptable salt or ester thereof is administered or used at least at a concentration of 1 mM, the '799
patent teaches orally dosed formulations of glycolic acid (see claim 2), where glycolic
formulation occurs in a range that encompasses the claimed concentration, a concentration of said acid or salt ranging from about 0.001 M to about 4M, see claim 4.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the primary reference of Tang to use anti-inflammatory AHAs to treat myocardial ischemia, where Perricone, demonstrates the anti-inflammatory property of the AHA, glycolic acid, in combination with the known myocardial ischemia treating drug, the calcium channel blocker, nifedipine, where ‘799 patent discloses the use of glycolic acid in a subject, and would rely on its teachings to arrive at concentration as taught by the art and claimed by Applicant.
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response states the Office Action's assertion that glycolic acid is equivalent to the malic acid and citric acid taught in Tang et al. with comparable anti-inflammatory activities is unsupported by any evidence.
The Attorney response states per US 5,516,799 Alliger, teaches away from the claimed invention, where it notes the efficacy of lactate and glycolic acid "is particularly surprising in light of the fact that similar compounds such as citric acid, sorbic acid and boric acid do not work at all."
The Attorney response states Toyoda et al. represents a further example of how various AHAs do not show equivalent biological effects and there appears to be no reason why a skilled person would assume that glycolic, malic and citric acids are functional equivalents with comparable anti-inflammatory activity.
In response, it is noted that other references in the art describe glycolic acid having an anti-inflammatory effect. Tang 20182 notes at Figure 3, page 7 of 12, glycolic acid had anti-inflammatory and photoprotective effect on cells exposed to UVB radiation.
The Attorney response states references post Perricone cast doubt on its findings. See Barrett MD, Quackwatch web page (https://quackwatch.org/1 llnd/perricone/), Katdbey et al. 2003 and Park 2002, where such corresponding arguments were accepted during the prosecution of granted parent patent US 11426372.
In response, it is noted that reference to parent patent US 11426372 and similar arguments overcoming the cited art are not necessarily applicable here as the parent ‘372 patent claims are directed to a method of treatment of ischemic insults with a composition comprising glycolic acid, whereas the child, divisional, examined claims are directed to a composition per se comprising glycolic acid and an ischemia reducing compound, such as a calcium channel blocker, nifedipine.
The Attorney response states Perricone et al. teaches that the apparent anti-inflammatory activity of glycolic acid may be attributed to its antioxidant properties which reduces the formation of free radicals, or chelate metals.
The Attorney response states Tang et al. provides a distinct mechanistic explanation for citric acid and L-malic acid, cardiomyocyte protective effect, anti-platelet aggregation AND anti-inflammatory effect, referencing especially Discussion section citric acid and L-malic acid increase phosphorylated (activated) Akt to prevent necrosis and apoptosis. The Attorney response goes into further detail with Tang and the mechanism of the PI3K/Akt pathway to state the mechanisms described in Perricone (antioxidant, free radical scavenger or by chelating iron) and those described in Tang are clearly different from one another.
The Attorney response states TNF-alpha is a common inflammatory response that is not in line with the teachings of cited prior art documents; Tang and Perricone have different mechanisms; and similar structures of AHA (glycolic acid, L-malic acid and citric acid) do not suggest they have similar biological effects (noting Fig 1 of Tang to support this statement). The Attorney response re-emphasizes these points at the page 14 of the Attorney response, first full paragraph, along with statements repeated from the ‘799 patent as an alleged teaching away; a restatement of the basis from Toyoda regarding that all AHAs do not show equivalent biological effects, see Fig. 4.
The Attorney response states it has demonstrated surprising and beneficial findings its pharmaceutical composition comprising GA (salt or ester) and ischemia reducing compound (calcium channel blocker nifedipine) have a therapeutic effect, over the cited prior art, where the response re-emphasizes its statements regarding Tang, Perricone and Kloner and that further, this claimed combination is NOT obvious over Tang, Perricone and Kloner, contrary to the Office Action.
In response, the selection of a known material based on its suitability for its intended use supports a prima facie obviousness determination. See, Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327 (1945) and MPEP § 2144.07. It is further noted that an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. See In re Fout, 675 F.2d 297 (CCPA 1982) and MPEP § 2144.06(II).
Initially, it is noted that the examined invention is directed to a pharmaceutical composition comprising glycolic acid (salts or esters) and an ischemia-reducing compound. Thus a teachings suggesting a basis to combine glycolic acid and ischemia-reducing compounds would be sufficient to support the rationale to combine the two and render the claims prima facie obvious.
As noted in the office action referenced in the Attorney comments themselves, the various taught alpha hydroxy acids (AHAs) are known to have anti-inflammatory activity.
The Attorney response details statements form the cited prior art to emphasize alternative mechanisms of actions to rebut the rationale to combine the references to render the invention prima facie obvious.
Noting MPEP 2145, Example 1, citing to PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342, 83 USPQ2d 1289 (Fed. Cir. 2007). Absolute predictability is not a necessary prerequisite to a case of obviousness, Id. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient, Id. The Federal Circuit concluded that “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304. See MPEP 2145, citing to PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342, 83 USPQ2d 1289 (Fed. Cir. 2007).
It is conceded that Applicant has demonstrated at paragraph 109 a prophetic vitro model; at paragraph 111 a prophetic in vivo ischemic limb model, where glycolic acid is expected to increase number of cardiomyocytes alive 24 hours after ischemia compared to controls; and at paragraph 112, a prophetic model of ischemic intestine; where glycolic acid is expected to reduce the extension of the ischemia and cell death of said in vitro cell models and in vivo limb and intestinal models.
However, even such experiments were actual and NOT prophetic models to demonstrate unexpected results to overcome prima facie case of obviousness already established, the examples provide no details as to dosing, they do not combine glycolic acid with nifedipine as elected and claimed, let alone provide any therapeutic data.
Without further details, these experimental models are neither within the scope of the examined claims, nor do they provide unexpected results to overcome the prima facie case, as they provide no data.
Conclusion and Correspondence
No claims are 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 CONTINUING DATA
This application is a DIV of 15/776,817 05/17/2018 PAT 11426372
15/776,817 is a 371 of PCT/EP2016/078061 11/17/2016
FOREIGN APPLICATIONS
EP 15003289.4 11/17/2015
2 Tang and Yang Dual Effects of Alpha-Hydroxy Acids on the Skin Molecules 2018, 23,863.
