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
Request for Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/30/2026 has been entered.
Review of Claim Status
Claims 1-3 were previously examined in the prior Office Action.
Upon amendment entrance, Claim 2 has been cancelled.
Claims 1 and 3 are currently pending investigation.
Priority
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This application, which discloses and claims only subject matter disclosed in prior Application No. 15/331,982 - filed 10/24/2016 (ABN) & Application No. 17/173,669 - filed 02/11/2021 (ABN), appears to claim only subject matter directed to an invention that is independent and distinct from that claimed in the prior application, and names the inventor or at least one joint inventor named in the prior application.
Information Disclosure Statements
No IDS was filed in this application.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Examiner Responses to Arguments/Amendments
The issues raised in the 03/30/2026 Office Action, are addressed below:
I. Claim Amendments –
In view of the Applicant’s amendment, the following was added to Claim 1:
A method of treating a disease sensitive to the specific agonism of the PPAR-gamma receptor in humans or animals, wherein said disease is selected from articular chondropathies,
the method consisting of administering Adelmidrol together with hyaluronic acid sodium salt and an isosmotic solvent buffered to pH 7.0 in a formulation for parenteral administration by injection for infiltration into a joint,
wherein Adelmidrol is contained in said formulations in a dosage from 1 mg to 7 g for the administration to a man (with a body weight of about 70 kg) or from 10 mg to 700 mg of the active ingredient by dose unit, wherein said articular chondropathies are articular chondropathies of mechanical, toxic, iatrogenic, degenerative origin or fibrogenesis of the articular cartilages.
II. Response to Affidavit/Declaration Under 37 USC §1.132 of Maria Federica Della Valle –
Examiner acknowledges Applicant submission of affidavit under 37 §1.132.
The declaration under 37 CFR 1.132 filed 03/30/2026 is insufficient to overcome the
rejections as set forth in the last Office action because:
First, the arguments and data presented do not establish the criticality of the method detailed in the instant case, nor do they correspond with what is recited in the claims. The data provided fails to show that the specific method limitations as broadly claimed produce an unexpected result or a distinct, practical advantage over the prior art. The Applicant has not demonstrated a clear nexus between the tested parameters and the claimed invention as a whole, leaving the scope of the claims unsupported by the evidence.
Second, Applicant refers in the arguments that Rheumatoid arthritis (RA) is not considered a chondropathy, and more specifically as an articular chondropathy. Because RA is an autoimmune inflammatory condition that severely damages joint cartilage, it is classified as a type of inflammatory articular chondropathy. Though not classified as a primary articular chondropathy in the same way as osteoarthritis (OA), it does cause as part of its disease process. RA and OA are fundamentally connected as articular chondropathies because both conditions lead to the irreversible degradation and loss of articular cartilage. Their molecular pathways and joint destruction mechanisms largely overlap.
Applicant further states in their argument that the Instant Application demonstrates: “the treatment of articular chondropathies with adelmidrol and hyaluronic acid sodium salt operates through a mechanism that directly influences cartilage homeostasis. This effect is not mediated by, nor does it depend on, modulation of inflammatory pathways or immune cell activity. Rather, it reflects a direct influence on the metabolic and regulatory governing cartilage homeostasis.”
In response to this argument above, Examiner wishes to remark both RA and OA are connected at the articular cartilage level through shared pathways of extracellular matrix (ECM) degradation, abnormal mechanical stress, and fibrogenic tissue remodeling. Both diseases ultimately converge in a damaging cycle that alters cartilage biomechanics and causes fibrotic-like structural change.
The prior art teaches a shared pathway through the inflammatory synovium triggering fibroblast-like synoviocytes (FLSs) to transform into myofibroblasts. This causes synovial fibrosis, generating severe joint stiffness, and perpetuates the secretion of pro-fibrotic factors like TGF-β and CTGF (Calcitonin Gene Relative Peptide). These cytokines like TNF, IL-1β, and IL-6 flood the joint micro-environment. Once activated, these synoviocytes produce matrix-degrading enzymes and inflammatory mediators, causing progressive cartilage erosion and joint degradation.
This relates to what is already known in the art about adelmidrol (known as N,N′-Bis(2-hydroxyethyl)nonanediamide and addressed in prior Office Actions) and it is known Adelmidrol is a palmitoylethanolamide (PEA) analogue and "entourage" enhancer. It targets neuroinflammation and prevents joint degradation. It acts as an Autacoid Local Injury Antagonist Amide (ALIAmide), regulating mast cell degranulation and breaking the destructive cycle that characterizes the articular chondropathies. Because endogenous PEA levels are characteristically depleted in joints affected by articular chondropathy, boosting PEA via adelmidrol treatment restores joint homeostasis and reduces pain sensitization.
Adelmidrol does not indiscriminately block all inflammatory pathways, but it selectively modulates key inflammatory signaling networks - notably PPAR-γ and NF-κB - leading to reduced expression of pro-inflammatory cytokines and mediators, thereby resolving inflammation in multiple disease contexts. So, adelmidrol does not simply “block” inflammatory pathways in a one-step manner; instead, it modulates multiple inflammatory signaling cascades to reduce inflammation. In that, Applicant has not shown criticality of viewing adelmidrol (Rather, it reflects a direct influence on the metabolic and regulatory governing cartilage homeostasis) in this manner.
Thus, Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
Third, the rejections based on the references cited in previous Office Actions, are maintained because a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Fourth, while adelmidrol actively stops the inflammatory cascade at the cellular level (down-modulating mast cells and reducing cartilage-destroying enzymes), hyaluronic acid simultaneously creates a microenvironment for tissue repair and provides essential biomechanical protection; information known and supported by the prior art.
Finally, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
III. Claim Rejections under 35 U.S.C. 103 –
Applicant' s arguments, filed 03/30/2026, with respect to the claims have been fully considered but they are not persuasive for the following reason(s):
The references for the 35 U.S.C. 103 rejection stand as reading, in totality, in teaching the scope of the Instant Case: a method of treating a disease sensitive to the specific agonism of the PPAR-gamma receptor in humans or animals, wherein said disease is selected from articular chondropathies, the method consisting of administering Adelmidrol together with hyaluronic acid sodium salt.
As such, the Applicant has not shown the criticality of the use of the adelmidrol on method of treating a disease sensitive to the specific agonism of the PPAR-gamma receptor in humans or animals that would differ from that seen already in the art.
Applicant argues: As attested to in the accompanying Rule 132 declaration, the anti-inflammatory mechanisms described in '842A are not mediated by activation of the PPAR-gamma receptor.
Applicant also states: this rejection is premised on an erroneous analogy between distinct pathologies and on an underestimation of the critical role of PPAR-gamma in the specific context of articular chondropathies. The claimed method exemplifies a technical contribution over the cited references which is unexpected.
In response to Applicant’s argument, Examiner responds that demonstrating that the observed therapeutic effects occur independently of the receptor requires utilizing specific pharmacological and genetic evidence - such as receptor antagonists, gene knockdown studies, and mutation models - to isolate and invalidate the PPAR-gamma pathway as the primary driver of the anti-inflammatory activity.
In this, the Instant Specification does not aid in contributing such information in identifying the true mediator by demonstrating pathway interactions. Also, with the scientific and experimental evidence provided and known in the art, adelmidrol (as a synthetic analog of PEA) acts as an active ligand-bound PPAR-γ modulator. It does not always need to bind to DNA, instead it directly binds to and deactivates pro-inflammatory transcription factors like NF-κB and AP-1. The drug may still rely on PPAR-γ to inhibit these inflammatory pathways, even without classic receptor activation.
This leads to maintaining the rejection based on the references cited in previous Office Actions, because a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
As such, Applicants argument is not persuasive.
IV. New RCE Non-Final Rejection –
Claim Objections
Claim 1 is objected to because it includes a parenthetical expression ("with a body weight of about 70 kg ") that does not enclose reference characters. Parenthetical expressions within the body of a claim are improper unless they are strictly used to enclose reference characters corresponding to elements in the detailed description and drawings.
Examiner suggests, in regards to the parenthetical phrase, to moving it to a wherein clause. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 1 and 3 is 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.
With respect to Claim 1, the claim is subject to multiple reasonable interpretations. The Claim recites [wherein Adelmidrol is contained in said formulations in a dosage from 1 mg to 7 g for the administration to a man (with a body weight of about 70 kg) or from 10 mg to 700 mg of the active ingredient by dose unit,]. This language renders the scope of the claim unclear because it is ambiguous for the following:
Interpretation 1: from 1 mg to 7 g for the administration to a man (with a body weight of about 70 kg).
Interpretation 2: from 10 mg to 700 mg for the administration to a man (with a body weight of about 70 kg).
Does the claim language require the “to a man” limitation with the body weight distribute to both alternatives? Or does the “to a man” limitation with the body weight apply only to the first alternative?
One could distribute to both alternatives or only to the first alternative, a person of ordinary skill in the art (POSITA) cannot determine with reasonable certainty the metes and bounds of the claimed invention. Because the claim can be read in these distinct ways, it is unclear which features are actually required, failing to distinctly point out the subject matter of the invention.
With respect to Claim 3, the claim is subject to multiple reasonable interpretations. The claim recites [The method according to claim 1, the said formulation consisting of: Adelmidrol 40 mg; Hyaluronic acid sodium salt 20 mg; and, Isosmotic solvent buffered to pH 7.0 q.s. to 5 mL]. This language renders the scope of the claim unclear since it is ambiguous for the following:
Interpretation 1: Does the limitation mean diluting the solution to a total of 5 mL of buffer?
Interpretation 2: Does the limitation mean using a total of 5 mL of buffer?
Additionally, the term q.s. is understood as quantum sufficiat or quantum satis, which translates to "a sufficient quantity" or "as much as is enough". This is unclear in light of the ambiguity above. What amount of which is represented as “a sufficient quantity”?
Because the claim can be read in these distinct ways, it is unclear which features are actually required, failing to distinctly point out the subject matter of the invention.
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.
Graham vs. Deere, Test for Obviousness
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.
Joint Inventors
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 and 3 are rejected under 35 U.S.C. 103 as being obvious over Francesco Della Valle, et al (US 5618842 A; hereinafter “App’842”; as evidenced by CAS-Adelmidrol) and in view of EpiTech Group S.R.I. (WO 2011/027373 A1; hereinafter “Pub’373”).
With respect to Claim 1, App’842 teaches:
a method of treating a disease sensitive to the specific agonism of the PPAR-gamma receptor in humans or animals (col. 2, lns. 13-17; claim 14);
wherein said disease is selected from articular chondropathies (human chronic inflammatory pathologies selected from the group consisting of chronic arthritis - chronic arthritis can cause focal damage to cartilage, particularly in its early to moderate stages - col. 25, lns. 23-25);
the method consisting of administering Adelmidrol (taught in the ‘App’842 prior art as N,N'-bis-(2-hydroxyethyl)-nonandiamide, seen in Ex. 3 on col. 8, lns. 60-67 to col. 9, lns. 1-19);
and an isosmotic solvent buffered to pH 7.0 (col. 17, lns. 22-27; ...intradermal injection on the auricular pinna with the compounds in question at the dose of 0.5 mg/kg, in a buffered aqueous solution at physiological pH; col. 20, lns. 1-5: Adult Sprague Dawley rats were injected in the ankle joint with 50 µg of 1% carrageenan physiological saline - 0.9% NaCl -or with physiological saline alone);
in a formulation for parenteral administration (col. 22, lns. 5-15; according to Merriam-Webster parenteral route refers to the parenteral route refers to administering medications or other substances to the body by bypassing the gastrointestinal (digestive) tract; this is typically done through injections) by injection for infiltration into a joint (col. 17, lns. 22-27);
wherein Adelmidrol (taught in the ‘App’842 prior art as N,N'-bis-(2-hydroxyethyl)-nonandiamide, seen in Ex. 3 on col. 8, lns. 60-67 to col. 9, lns. 1-19)
is contained in said formulations in a dosage from 1 mg to 7 g for the administration to a man (with a body weight of about 70 kg) or from 10 mg to 700 mg of the active ingredient by dose unit (acceptable therapeutic range being between 0.1 mg/kg to 20 mg/kg - col. 22, lns. 15-20 which reads on the claimed range - and - 50 mg of the active ingredient by dose unit - which reads on the claimed range; Example 4, col 23, lns. 38-51).
wherein said articular chondropathies are articular chondropathies of mechanical, toxic, iatrogenic, degenerative origin or fibrogenesis of the articular cartilages (App’842 teaches human chronic inflammatory pathologies selected from the group consisting of chronic arthritis… - chronic arthritis can cause focal damage to cartilage, particularly in its early to moderate stages - col. 25, lns. 23-25. As chronic arthritis causes focal damage to cartilage, adelmidrol administration helps regulate and downgrade pro-inflammatory signaling molecules (like Interleukin-1β) and metalloproteinases that actively mediate cartilage destruction, it reads on the claims).
App’842 fails to teach with respect to claim 1, an adelmidrol formulation together with hyaluronic acid sodium salt. However, App’842 does teach an intradermal injection (reading on parenteral administration) containing adelmidrol at the dose of 0.5 mg/kg, in a buffered aqueous solution at physiological pH (col. 25, lns. 23-25). App’842 also teaches that compositions containing active ingredients comprises formulations suitable for excipients pharmacologically acceptable suitable for the same applications, as well new excipients able to improve the delivery of these compounds to the site of action. This gives understanding that additional excipients like hyaluronic acid would be beneficial as an addition.
Pub’373 teaches treatment formulations in association with a palmitoylethanolamide (PEA) parenteral administration taken in association with hyaluronic acid sodium salt (pg. 33, lns. 15-20 to pg. 34, lns. 1-7).
Adelmidrol is a synthetic palmitoylethanolamide analogue and as such, one skilled in the art could apply prong B of KSR. Pub’373 teaches palmitoylethanolamide has great efficacy in the treatment of pain and inflammation. Adelmidrol, a diamide derivative of azelaic acid-is one these analogues. As such substituting PEA with the compound of adelmidrol, as seen in Pub’373, one would expect success since it is one of the analogues. As evidenced by App’842, all pieces of prior art are related to treatment (Adelmidrol) to alleviate pain through the drug’s mechanism of action. This too, as evidenced by the work above has similar utility. In combining the teachings of App’842 with those of Pub’373, it can be taken into account that the formulations combined would lead to improved formulation.
With respect to Claim 3, App’842 teaches the formulation of adelmidrol in formulation as detailed above in Claim 1. App’842 continues to teach the method comprising administering Adelmidrol as seen in Example 3 (col. 8-9, Example 3) N,N'-bis-(2-hydroxyethyl)-nonandiamide, also known as Adelmidrol)) and Adelmidrol contained in said formulations in a desired dosage.
App’842 fails to teach an adelmidrol formulation together with hyaluronic acid sodium salt. However, App’842 does teach an intradermal injection (reading on parenteral admin.) containing adelmidrol at the dose of 0.5 mg/kg, in a buffered aqueous solution at physiological pH (col. 25, lns. 23-25). App’842 also teaches that compositions containing active ingredients comprises formulations suitable for excipients pharmacologically acceptable suitable for the same applications, as well new excipients able to improve the delivery of these compounds to the site of action. This gives understanding that additional excipients like hyaluronic acid would be beneficial as an addition.
Pub’373 teaches formulations made in the treatment of PEA “adapted for a parenteral administration by injection. The formulations for the injections can be presented in the form of a single dose, for example, in ampoules, with the addition of a preservative. The compositions can be in such a form as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain prescribed agents, such as · suspending agents, stabilizers, and/ or dispersants (Formulation examples, starting pg. 31-36). The administration is taken in association with hyaluronic acid sodium salt (pg. 33, lns. 15-20 to pg. 34, lns. 1-7) in association with a palmitoylethanolamide.
Adelmidrol is a synthetic palmitoylethanolamide analogue and as such, one skilled in the art could apply prong B of KSR. Pub’373 teaches palmitoylethanolamide has great efficacy in the treatment of pain and inflammation. Adelmidrol, a diamide derivative of azelaic acid-is one these analogues.
As evidenced by App’842, the prior art is related to treatment of pain which is caused through the mechanism of actions known in the art of adelmidrol. Pub’373 teaches treatment formulations in association with a palmitoylethanolamide (PEA) parenteral administration taken in association with hyaluronic acid sodium salt (pg. 33, lns. 15-20 to pg. 34, lns. 1-7). As such substituting palmitoylethanolamide (PEA) with adelmidrol, according to KSR-Prong B, one would expect success.
As such, the dosage is viewed as a result-effective concentration. One can use routine optimization to arrive at different concentrations of adelmidrol and hyaluronic acid through motivation and suggestion of several formulations listed in the above prior arts. Such routine optimization to arrive at the precise dosage needed is common for a skilled chemist. Hence variables that alter the rate of reactivity, the production of effects and the final result of desired activation/inhibition, treating/ameliorating symptoms desired is result effective.
In this case, using the dosing ranges and method of administration as taught by both App’842 and Pub’373 would lead to safe ranges in the treatment in humans. One skilled in the art would expect success because dosage is result-effective if a skilled artisan would naturally adjust it to achieve better results. The compounds and references relate to treating articular chondropathies. The claimed dosage has not been shown to achieve a radically different, unexpected outcome rather than just a predictable, proportional change.
One skilled in the art could have combined the elements by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395. Since one would be motivated with the success of the prior art, it would have been prima facie obvious to arrive at the claimed range because finding proper dosage is one step closer to individualized personal treatment for articular chondropathies. MPEP 2144.05 (incorporated by reference herein).
Conclusion
Claims 1 and 3 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Josmalen M. Ramos-Lewis whose telephone number is (571)-272-0084. The examiner can normally be reached M-F 9:30-5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Josmalen M. Ramos-Lewis, Ph.D.
Patent Examiner
Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
Prosecution Insights