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 .
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 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.
Priority
The instant application, filed 01/27/2023, claims domestic benefit to US provisional application 63/303,731, filed 01/27/2022.
Status of Application, Amendments, and/or Claims
Applicant’s amendment of 01/13/2026 is acknowledged. Claims 1, 3-4, 10, 13, and 16 are amended and claims 2 and 9 are cancelled. Claims 1, 3-8, and 10-18 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/09/2026 (2) are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Withdrawn Objections and Rejections
In the office action of 10/14/2025,
The sequence disclosure was objected to. Applicant’s amendment to fig. 14 to include a SEQ ID NO with the recited peptide has overcome the objection and the objection is withdrawn.
The drawings were objected to for minor informalities. Applicant’s amendment to the drawings to clearly show the left portion of Fig. 1D has overcome the objection and the objection is withdrawn.
Claim 10 was objected to. Applicant’s amendment to the claim to add a comma between parthenolide and micheliolide has overcome the objection and the objection is withdrawn.
Claims 1-3, 8, and 12-18 were rejected under 35 USC 102(a)(1) over Chen. Applicant’s amendment to the independent claims to limit the targeting ligand as specifically binding to TRAP has overcome the rejections and the rejections are withdrawn.
Claims 1-8 and 11 were rejected under 35 USC 102(a)(1) over Wang. Applicant’s amendment to the independent claim to limit the therapeutic agent to those selected has overcome the rejections and the rejections are withdrawn.
Claims 2 and 9 were rejected under 35 USC 103 and on the grounds of nonstatutory double patenting. The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
The following grounds of objections and rejections are maintained.
Drawing objections
The drawings filed 06/09/2023 contain colored figures without an approved petition under 37 CFR 1.84(a)(2). Filing of black and white/grey scale figures or an approved petition is required. It is noted that a petition for colored drawings was filed on 01/13/2026, but has not yet been reviewed.
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.
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, 3-8, 11-13, 15-16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Ackerman, J.E., et al (2019) Cell non-autonomous functions of S100a4 drive fibrotic tendon healing eLife 8; e45342; 1-23 in view of Wang, Y., et al (2017) Fracture-targeted delivery of β-Catenin Agonists via Peptide-functionalized nanoparticles augments fracture healing ACS Nano 11; 9445-9458 and Wu, C.L., et al (2020) The role of macrophages in osteoarthritis and cartilage repair Osteoarthritis and Cartilage 28; 544-554.
Ackerman teaches that tendons are composed primarily of a dense, highly aligned collagen extracellular matrix and connect muscle to bone to transmit mechanical forces throughout the body. Following injury, tendon demonstrates limited regenerative potential and heals through a scar-mediated fibrotic process involving abundant, disorganized ECM deposition. While scar tissue can impart some mechanical strength to the healing tissue, it is also mechanically inferior to native tendon and dramatically impairs normal tendon function resulting in substantial morbidity (page 1, paragraph 1). Ackerman teaches that the identification of pro-regenerative approaches to improve tendon healing is critically important as the fibrotic healing response impairs physical function. In the presented study, the hypothesis that S100a4 haploinsufficiency or inhibition of S100a4 signaling improves tendon function following acute injury and surgical repair in a murine model was tested. It is demonstrated that S100a4 drives fibrotic tendon healing primarily through a cell non-autonomous process, with S100a4 haploinsufficiency promoting regenerative tendon healing. Moreover, inhibition of S100a4 signaling via antagonism of its putative receptor, RAGE, also decreased scar formation. Mechanistically, S100a4 haploinsufficiency decreases myofibroblast and macrophage content at the site of injury with both cell populations being key drivers of fibrotic progression. Using a combination of genetic mouse models, small molecule inhibitors, and in vitro studies, Ackerman demonstrates S100a4 as a novel promising therapeutic candidate to improve tendon function after acute injury (abstract).
Ackerman teaches that S100a4 is a novel target to improve tendon healing and demonstrates the efficacy of pharmacological inhibition of S100a4 signaling to improve functional outcomes during healing (page 2, paragraph 2) and studied the use of the RAGE inhibitor, RAGE antagonist peptide (RAP) (page 8, paragraph 2).
Ackerman further teaches that macrophages play an essential role in wound healing and S100a4 is a potent chemokine and regulator of macrophage chemotaxis (page 11, paragraph 3). Given the fibrotic nature of scar-mediated tendon healing, and the ability of macrophages to modulate multiple aspects of the fibrotic process, changes in macrophage content, and polarization during the proliferative phase of healing in WT and S100a4GFP/+- mice was examined. Taken together, the data acquired suggest that additional populations of cells expressing S100a4 during tendon healing, and the predominant role for S100a4+ macrophages, may be during the early phases of healing (page 6, paragraph 2).
Ackerman teaches that anti-inflammatory administration during the acute inflammatory phase of tendon healing is effective at reducing scar formation, but causes marked reductions in mechanical properties. Taken together, this data supports the importance of timing treatment to modulate fibrotic tendon healing, particularly as it relates to S100a4 inhibition (page 13, paragraph 2). Peak expression of S100a4 post-surgery suggests that the prime effects of S100a4 may occur during the early inflammatory-proliferative phases of healing. The time dependent effects S100a4-cell depletion suggest that there is likely an optimal therapeutic window for S100a4 inhibition (page 14, paragraph 3).
Ackerman concludes that the studies presented define the tremendous potential of inhibition of S100a4 signaling as a therapeutic approach to promote regenerative tendon healing (page 14, paragraph 3).
Ackerman, however, does not disclose that the S100a4 or RAGE inhibitor is comprised in composition for controlled local delivery of the therapeutic agent to the injured tendon that comprises a targeting ligand that specifically binds TRAP tethered to a polymer as claimed.
Wang teaches a fracture targeted poly(styrene-alt-maleic anhydride)-b-poly(styrene) (PSMA-b-PS) nanoparticle delivery system using the β-catenin agonist, 3-amino-6-(4-((4-methylpiperazin-1-yl)-sulfonyl)phenyl)-N-(pyridin-3-yl)pyrazine-2-carboxamide (AZD2858, a GSK-3β inhibitor). Wang further teaches that a peptide with high affinity for tartrate-resistant acid phosphate (TRAP) was introduced to the NPs (page 9446, right column, paragraph 2). Scheme 1 provides the synthesis of PSMA-b-PS, the self-assembly of the deblock copolymers into micelle NPs via solvent exchange method, and the functionalization of PSMA-b-PS with peptide targeting moieties. The scheme shows that the peptide targeting moiety is tethered to the polymer and is TBP with a structure of NH2-TPLSYLKGLVTVG-COOH (page 9446, Scheme 1); a peptide sequence which is identical to that of instant SEQ ID NO: 1, as shown in the ABSS alignment below:
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727
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Scheme 2 of Wang (page 9447) demonstrates the polymer nanoparticle tethered to the TRAP-binding peptide (TBP) targeting group with a Wnt/β-catenin agonist.
Wang further teaches that the use of drug delivery systems, such as nanoparticles (NP) address challenges associated with suboptimal pharmacokinetics and biodistribution of therapeutics as they increase small molecule drug solubility, stability, and circulation time. Wang teaches that PSMA-b-PS-based NPs have shown excellent loading and sustained release of multiple hydrophobic drugs, and offer vast chemical versatility for functionalization with various targeting ligands for tissue/cell-specific affinity due to a myriad of maleic anhydride carboxylic acid groups (page 9446, right column, paragraph 2).
Wu teaches that tendon is a fibrous, connective tissue bridging muscles to bone. Tendons are composed mainly of collagen fibrils and their main function is to respond to mechanical forces, providing joint flexion and stability. The presence of M1-like macrophages in conjunction with loading may facilitate tendon repair compared to injured tendon without loading. Determining the time-course and balance of pro- and anti-inflammatory macrophages is likely critical in maintaining homeostasis and joint integrity. When macrophages are modulated using extracellular exosome vesicles to encourage a lower ratio of M1-like to M2-like macrophages, healing is improved in the Achilles tendon (page 549).
Wu teaches that pro-inflammatory macrophages express degradative enzymes including tartrate-resistant acid phosphatase (TRAP) (page 549, left column, paragraph 3). Wu further teaches that M1-like macrophages are pro-inflammatory (page 549, right column, paragraph 3).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of treating tending injury and promoting tendon regeneration taught by Ackerman to use the TRAP targeting PSMA-b-PS based controlled targeted delivery system disclosed by Chen, for the delivery of a S100a4 or RAGE inhibitor based on the teachings of Wu. An ordinarily skilled artisan would have been motivated to use a controlled targeted delivery system in order to increase small molecule drug solubility, stability, and circulation time while directly targeting the therapeutic to the site of tendon injury. An ordinarily skilled artisan would have had a reasonable expectation of success in using the TRAP targeting PSMA-b-PS nanoparticle as both Ackerman and Wu teach the presence of pro-inflammatory macrophages in sites of tendon injury and Wu teaches that pro-inflammatory macrophages express TRAP.
This conclusion of obviousness is further supported by KSR (C) use of a known technique to improve similar devices in the same way. See MPEP 2143. In this case, Ackerman teaches the use of a RAGE antagonist in the treatment of tendon injury and regeneration. Wang demonstrates an improvement over systemic therapy by the inclusion of the therapeutic in a targeting polymer. One of ordinary skill in the art could have applied this known improvement technique in the same way to the base methods of Ackerman and the result would have been the predictable targeted delivery of the RAGE antagonist to the site of tendon injury.
Regarding claims 15 and 18, It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use the teachings of Ackerman as a guide and optimization that was routine in the art to determine the optimal therapeutic window for administration of the composition taught by the combination of Ackerman, Wang, and Wu.
MPEP 2144.05 (II) A. states that "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”.
In this case, as discussed in detail above, Ackerman teaches the timing of treatment to modulate fibrotic tendon healing, particularly as it relates to S100a4 inhibition, is important. Ackerman also teaches that anti-inflammatory administration during the acute inflammatory phase is effective at reducing scar formation, but causes marked reductions in mechanical properties and that peak expression of S100a4 suggests that the prime effects of S100a4 may occur during the early inflammatory – proliferative phases of healing. Ackerman further teaches that there is likely an optimal therapeutic window for S100a4 inhibition (page 13, paragraph 2; page 14, paragraph 2). One of ordinary skill in the art would be able to use these teachings as a starting point in determining the optimal therapeutic window for administration of the composition.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Ackerman, J.E., et al (2019) Cell non-autonomous functions of S100a4 drive fibrotic tendon healing eLife 8; e45342; 1-23 in view of Wang, Y., et al (2017) Fracture-targeted delivery of β-Catenin Agonists via Peptide-functionalized nanoparticles augments fracture healing ACS Nano 11; 9445-9458 and Wu, C.L., et al (2020) The role of macrophages in osteoarthritis and cartilage repair Osteoarthritis and Cartilage 28; 544-554 as applied to claims 1, 8, and 9 above, and in further view of Hudson, B.I., and M.E. Lippman (2018) Targeting RAGE signaling in inflammatory disease Ann. Rev. Med. 69; 349-364.
The combination of Ackerman, Wang, and Wu teach the composition of claim 8 as discussed in detail above.
The combination of Ackerman, Wang, and Wu, however, do not disclose that the therapeutic agent is selected from those recited in instant claim 10.
Hudson teaches that the receptor for advanced glycation end-products (RAGE) is a multiligand pattern recognition receptor implicated in diverse chronic inflammation stages. RAGE binds and mediates the cellular response to a range of damage-associated molecular pattern molecules (DAMPs) including S100s. Blocking RAGE signaling in cell and animal models has revealed that targeting RAGE impairs inflammatory responses and is relevant in inflammatory disease (abstract).
Hudson teaches small molecule inhibitors that target either the extracellular ligand-binding site of RAGE, or, more recently, the intracellular signaling domain of RAGE (page 358, RAGE inhibitors). Hudson teaches extracellular inhibitors including TTP488, also known as PF-04494700 or azeliragon, as well as FPS-ZMI (pages 358-359, Extracellular inhibitors of RAGE).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the composition taught by the combination of Ackerman, Wang, and Wu by substituting the S100a4 or RAGE inhibitors for azeliragon or FPS-ZMI as disclosed by Hudson. It would have been obvious to use one of the inhibitors disclosed by Hudson as Hudson demonstrates that they were known small molecule inhibitors that bind to the extracellular ligand binding site of RAGE inhibiting the binding of ligands including S100s. An ordinarily skilled artisan would have had a reasonable expectation of success as Ackerman teaches the antagonism of RAGE for fibrotic tendon healing.
Claims 14 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Ackerman, J.E., et al (2019) Cell non-autonomous functions of S100a4 drive fibrotic tendon healing eLife 8; e45342; 1-23 in view of Wang, Y., et al (2017) Fracture-targeted delivery of β-Catenin Agonists via Peptide-functionalized nanoparticles augments fracture healing ACS Nano 11; 9445-9458 and Wu, C.L., et al (2020) The role of macrophages in osteoarthritis and cartilage repair Osteoarthritis and Cartilage 28; 544-554 as applied to claims 13 and 16 above, and in further view of Snedeker, J.G., and J. Foolen (2017) Tendon injury and repair – A perspective on the basic mechanisms of tendon disease and future clinical therapy Acta Biomaterialia 63; 18-36.
The combination of Ackerman, Wang, and Wu teach the methods of claims 13 and 16 as discussed in detail above.
The combination of Ackerman, Wang, and Wu, however, do not disclose that the tendon injury is selected from those recited in instant claims 14 and 17.
Snedeker teaches that tendon is an intricately organized connective tissue that efficiently transfers muscle force to the bony skeleton. Its structure, function, and physiology reflect the extreme, repetitive mechanical stresses that tendon tissues bear. These mechanical demands also lie beneath high clinical rates of tendon disorders and present daunting challenges for clinical treatment of these ailments (abstract). Snedeker teaches that the most common clinical tendon condition is tendinopathy, related to the overuse and characterized by an underlying state of tissue degeneration that is often painful. Clinical treatment of tendinopathy focuses on active or passive physiotherapy, or anti-inflammatory drugs. The net outcome, however, typically results in prolonged suffering of the patient with a substantial loss of personal productivity, reflecting the fact that tendons play a central role in normal human movement (page 19, left column, paragraph 1).
Snedeker further teaches that tendon damage is conceptually dividable into two subclasses including acute damage, which is traumatic damage of previously healthy tissue, and chronic, degenerative damage. Acute injuries, e.g. laceration of the finger flexor tendons, involve a sudden external disruption of originally healthy tendons. Although such injuries often heal with acceptable recovery of function, the tissue quality of biological and/or surgical repair rarely returns to preinjury level. Tendon ruptures may also occur spontaneously during activities of daily living. It is now widely viewed that such tendon ruptures can be attributed to underlying accumulated tissue damage associated with degenerative tissue remodeling processes (page 27, left column, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use the method of promoting tendon regeneration and treatment of tendon injury disclosed by the combination of Ackerman, Wang, and Wu for the treatment of known tendon injuries including ruptures and tendinopathy as taught by Snedeker. An ordinarily skilled artisan would have been motivated to apply the treatment to these disorders in order to achieve pro-regenerative approaches to improve tendon healing thereby limiting suffering and restoring personal productivity. An ordinarily skilled artisan would have had a reasonable expectation of success as Snedeker demonstrates that ruptures and tendinopathy are a result of degeneration of the tendons and the methods taught by the combination of Ackerman, Wang, and Wu are regenerative methods for tendon injury.
Response to Arguments
Applicant’s arguments in the response filed 01/13/2026 have been fully considered but are not persuasive.
With regards to the rejection of the claims under 35 USC 103 over Ackerman, Wang, and Wu, applicant argues that a skilled artisan would have no expectation of success in modifying the method of Ackerman to incorporate the targeting ligand of Wang. Applicant argues that the applied references do not suggest that any location of the body having TRAP positive macrophages can be targeted for therapeutic delivery via a TRAP binding targeting ligand. Applicant argues that without the aid of hindsight bias, there would be no expectation that the TRAP binding ligand of Wang would be suitable for the controlled local delivery of a therapeutic to a tendon. Applicant argues that the mere presence of TRAP positive macrophages in or near a tissue site provides no expectation of success without appropriate experimentation.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Additionally, the rejection does not rely on the targeting of TRAP positive macrophages in any location of the body, as suggested by applicant, but rather specific location(s) taught by the prior art. As discussed in detail in the rejection, Ackerman and Wu teach that pro-inflammatory macrophages are present in sites of tendon injury and Wu teaches that these macrophages express TRAP demonstrating that it was known that TRAP expressing cells were present in areas of tendon injury. The teachings of Wang motivate the use of targeted delivery of therapeutics teaching that the use of such delivery systems can increase small molecule solubility, stability, and circulation time. Wang also demonstrates that targeting TRAP had been considered in the prior art and that the use of TRAP targeting PSMA-b-PS based delivery systems had been generated. Based on these teachings, an ordinarily skilled artisan would have reasonably expected that TRAP expressing cells could be targeted for therapeutic delivery, including those acknowledged by Wu as being present at the site of tendon injury. Applicant does not provide any evidence to suggest that the TRAP targeting delivery system of Wang would not have been expected to be capable of targeting TRAP expressing cells known to be present near sites of tendon injury.
In regards to applicant’s arguments that the combination of applied references do not experimentally demonstrate the targeting of TRAP in the treatment of tendon injuries, the standard of obviousness is a reasonable expectation of success and conclusive proof of efficacy is not required. See MPEP 2143.02 (I) which states that “conclusive proof of efficacy is not required to show a reasonable expectation of success” and "the expectation of success need only be reasonable, not absolute".
As the prior art teaches that TRAP is expressed in areas of tendon injury and that TRAP has been considered for targeted therapeutic delivery, an ordinarily skilled artisan would have had a reasonable expectation of success. Additionally, the rejection is further supported by KSR(C), use of a known technique to improve similar devices in the same way as Wang demonstrates an improvement over systemic therapy by the inclusion of the therapeutic in a targeting polymer which could be applied to the therapeutics taught by Ackerman based on the teachings of Wu.
Applicant further argues that a skilled artisan would understand the unpredictability of using targeting ligands for controlled and local delivery to a tissue. Applicant argues that the present application shows, through appropriate experimentation, that a TRAP binding targeting ligand may be used to target and deliver an appropriate therapeutic to tendon. Applicant cites instant Figs. 7-13 as depicting experimental results showing such targeting.
While it is appreciated that applicant has demonstrated that a TRAP targeting ligand can be used to deliver therapeutics to tendons, conclusive proof of efficacy from the prior art is not required in order to establish obviousness as discussed above. As such, none of the applied references are required to experimentally demonstrate the claimed composition or method in order to establish that there would have been a reasonable expectation of success.
Furthermore, while applicant argues that there is unpredictability in using targeting ligands for controlled and local delivery to a tissue, applicant does not provide any evidence to support such speculation or to establish that targeting TRAP would not have been predictable or that the claimed targeting results in an outcome that would not have been expected. This is particularly the case as the prior art, particularly Wang, demonstrates that TRAP tethered polymers had been considered in the art for the targeted delivery of therapeutics.
With regards to the references Hudson and Snedeker, applicant argues that Hudson and Snedeker do not support a reasonable expectation of success in arriving at the invention of claim 1.
Applicant’s arguments concerning the combination of Ackerman, Wang, and Wu were not persuasive for the reasons discussed in detail above. As such, Hudson and Snedeker are not required to provide a reasonable expectation of success in arriving at instant claim 1. Rather, Hudson and Snedeker are applied to demonstrate that further limitations of the instantly claimed compositions and methods would have been obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 9,949,950 B2
Claims 1, 3-8, and 10-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 9,949,950 B2 in view of Ackerman, J.E., et al (2019) Cell non-autonomous functions of S100a4 drive fibrotic tendon healing eLife 8; e45342; 1-23, Wu, C.L., et al (2020) The role of macrophages in osteoarthritis and cartilage repair Osteoarthritis and Cartilage 28; 544-554, Hudson, B.I., and M.E. Lippman (2018) Targeting RAGE signaling in inflammatory disease Ann. Rev. Med. 69; 349-364, and Snedeker, J.G., and J. Foolen (2017) Tendon injury and repair – A perspective on the basic mechanisms of tendon disease and future clinical therapy Acta Biomaterialia 63; 18-36.
US’950 claims a composition for controlled local delivery of a therapeutic agent to bone, the composition comprising a therapeutic-tethered macromer comprising a targeting ligand and a therapeutic agent tethered to a polymer US’950 further claims that the targeting peptide specifically binds to tartrate-resistant acid phosphatase (TRAP) and comprises the amino acid sequence of SEQ ID NO: 1 (claim 1), which is identical to instant SEQ ID NO: 1.
The therapeutic is tethered to the polymer via at least one degradable tether and the polymer comprises poly(ethylene glycol) (PEG) methacrylate (claim 7).
The claims of US’950 differ from the instantly claimed invention in that the instantly claimed invention comprises a therapeutic that promotes tendon regeneration and claims methods of promoting tendon regeneration and treating tendon injury.
The teachings of Ackerman, Wu, Hudson, and Snedeker are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the composition claimed by US’950 by using a therapeutic agent that promotes tendon regeneration, for instance a RAGE inhibitor as taught by Ackerman, including azeliragon or FPS-ZMI as taught by Hudson, in place of the agent that promotes bone repair and administering the therapeutic in a method of treating tendon injury as taught by Ackerman, including tendinopathy or rupture as taught by Snedeker, based on the teachings of Wu.
An ordinarily skilled artisan would have been motivated to use a controlled targeted delivery system in the treatment of tendon injury in order to increase small molecule drug solubility, stability, and circulation time while directly targeting the therapeutic to the site of tendon injury. An ordinarily skilled artisan would have had a reasonable expectation of success in using the TRAP targeting PSMA-b-PS nanoparticle as both Ackerman and Wu demonstrate the presence of pro-inflammatory macrophages in sites of tendon injury and Wu teaches that pro-inflammatory macrophages express TRAP.
It would have been obvious to use one of the inhibitors disclosed by Hudson as Hudson demonstrates that they were known small molecule inhibitors that bind to the extracellular ligand binding site of RAGE inhibiting the binding of ligands including S100s. An ordinarily skilled artisan would have had a reasonable expectation of success as Ackerman teaches the antagonism of RAGE for fibrotic tendon healing.
An ordinarily skilled artisan would have been motivated to apply the treatment to the disorders taught by Snedeker in order to achieve pro-regenerative approaches to improve tendon healing thereby limiting suffering and restoring personal productivity. An ordinarily skilled artisan would have had a reasonable expectation of success as Snedeker demonstrates that ruptures and tendinopathy are a result of degeneration of the tendons and the methods are regenerative methods for tendon injury.
Regarding claims 15 and 18, It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use the teachings of Ackerman as a guide and optimization that was routine in the art to determine the optimal therapeutic window for administration of the composition. See MPEP 2144.05 (II) A. In this case, as discussed in detail above, Ackerman teaches the timing of treatment to modulate fibrotic tendon healing, particularly as it relates to S100a4 inhibition, is important. Ackerman also teaches that anti-inflammatory administration during the acute inflammatory phase is effective at reducing scar formation, but causes marked reductions in mechanical properties and that peak expression of S100a4 suggests that the prime effects of S100a4 may occur during the early inflammatory – proliferative phases of healing. Ackerman further teaches that there is likely an optimal therapeutic window for S100a4 inhibition (page 13, paragraph 2; page 14, paragraph 2). One of ordinary skill in the art would be able to use these teachings as a starting point in determining the optimal therapeutic window for administration of the composition.
US 10,195,284 B2
Claims 1, 3-8, and 10-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of U.S. Patent No. 10,195,284 B2 in view of Ackerman, J.E., et al (2019) Cell non-autonomous functions of S100a4 drive fibrotic tendon healing eLife 8; e45342; 1-23, Wu, C.L., et al (2020) The role of macrophages in osteoarthritis and cartilage repair Osteoarthritis and Cartilage 28; 544-554, Hudson, B.I., and M.E. Lippman (2018) Targeting RAGE signaling in inflammatory disease Ann. Rev. Med. 69; 349-364, and Snedeker, J.G., and J. Foolen (2017) Tendon injury and repair – A perspective on the basic mechanisms of tendon disease and future clinical therapy Acta Biomaterialia 63; 18-36.
US’284 claims a composition for controlled local delivery of a therapeutic agent to bone, the composition comprising a therapeutic-tethered macromer comprising a targeting ligand and a therapeutic agent tethered to a polymer, wherein the polymer is selected from the group consisting of PEG methacrylate and PSMA-b-PS (claim 1). US’284 further claims that the targeting domain comprises a targeting peptide that specifically binds to TRAP and comprises the amino acid sequence of SEQ ID NO: 1 (claims 9 and 14), which is identical to instant SEQ ID NO: 1. US’284 further claims a method of promoting bone formation at a site in need thereof comprising administering the composition (claims 35-37).
The claims of US’284 differ from the instantly claimed invention in that the instantly claimed invention comprises a therapeutic that promotes tendon regeneration and claims methods of promoting tendon regeneration and treating tendon injury.
The teachings of Ackerman, Wu, Hudson, and Snedeker are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the composition claimed by US’284 by using a therapeutic agent that promotes tendon regeneration, for instance a RAGE inhibitor as taught by Ackerman, including azeliragon or FPS-ZMI as taught by Hudson, in place of the agent that promotes bone repair and administering the therapeutic in a method of treating tendon injury as taught by Ackerman, including tendinopathy or rupture as taught by Snedeker, based on the teachings of Wu.
An ordinarily skilled artisan would have been motivated to use a controlled targeted delivery system in the treatment of tendon injury in order to increase small molecule drug solubility, stability, and circulation time while directly targeting the therapeutic to the site of tendon injury. An ordinarily skilled artisan would have had a reasonable expectation of success in using the TRAP targeting PSMA-b-PS nanoparticle as both Ackerman and Wu demonstrate the presence of pro-inflammatory macrophages in sites of tendon injury and Wu teaches that pro-inflammatory macrophages express TRAP.
It would have been obvious to use one of the inhibitors disclosed by Hudson as Hudson demonstrates that they were known small molecule inhibitors that bind to the extracellular ligand binding site of RAGE inhibiting the binding of ligands including S100s. An ordinarily skilled artisan would have had a reasonable expectation of success as Ackerman teaches the antagonism of RAGE for fibrotic tendon healing.
An ordinarily skilled artisan would have been motivated to apply the treatment to the disorders taught by Snedeker in order to achieve pro-regenerative approaches to improve tendon healing thereby limiting suffering and restoring personal productivity. An ordinarily skilled artisan would have had a reasonable expectation of success as Snedeker demonstrates that ruptures and tendinopathy are a result of degeneration of the tendons and the methods are regenerative methods for tendon injury.
Regarding claims 15 and 18, It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use the teachings of Ackerman as a guide and optimization that was routine in the art to determine the optimal therapeutic window for administration of the composition. See MPEP 2144.05 (II) A. In this case, as discussed in detail above, Ackerman teaches the timing of treatment to modulate fibrotic tendon healing, particularly as it relates to S100a4 inhibition, is important. Ackerman also teaches that anti-inflammatory administration during the acute inflammatory phase is effective at reducing scar formation, but causes marked reductions in mechanical properties and that peak expression of S100a4 suggests that the prime effects of S100a4 may occur during the early inflammatory – proliferative phases of healing. Ackerman further teaches that there is likely an optimal therapeutic window for S100a4 inhibition (page 13, paragraph 2; page 14, paragraph 2). One of ordinary skill in the art would be able to use these teachings as a starting point in determining the optimal therapeutic window for administration of the composition.
Response to Arguments
In the response of 01/13/2026, applicant requests that the nonstatutory double patenting rejections be held in abeyance as no claims have been allowed in the instant application.
As no allowable claims are identified in the instant office action, the rejections under nonstatutory double patenting are maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693