Patent Application 15848518 - SYSTEMS AND METHODS FOR SYMPATHETIC

Title: SYSTEMS AND METHODS FOR SYMPATHETIC CARDIOPULMONARY NEUROMODULATION

Application Information

Invention Title: SYSTEMS AND METHODS FOR SYMPATHETIC CARDIOPULMONARY NEUROMODULATION
Application Number: 15848518
Submission Date: 2025-04-09T00:00:00.000Z
Effective Filing Date: 2017-12-20T00:00:00.000Z
Filing Date: 2017-12-20T00:00:00.000Z
National Class: 514
National Sub-Class: 001000
Examiner Employee Number: 97534
Art Unit: 1675
Tech Center: 1600

Rejection Summary

102 Rejections: 0
103 Rejections: 2

Cited Patents

No patents were cited in this rejection.

Office Action Text

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
Claims 84-89, 93-98, and 102 are under consideration in the instant Office Action.

Modified Rejections Necessitated by Amendment
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.

Claims 84, 85, 93-98, and 102 are rejected under 35 U.S.C. 103 as being unpatentable over Seward (US 20110104061; IDS 2/9/18 citation 24) in view of Cai (in PTO-892 filed 11/20/2020) and further in view of Tan (in PTO-892 filed 12/15/2021).
Regarding claim 84, Seward teaches methods of neuromodulation, specifically denervation/sympathectomy (paragraph 19). Seward teaches that one means of inhibiting the relevant nerves/neurons is by administering ethanol (“phenol and ethanol have also been used to produce chemical sympathectomy and are also useful in the methods of this invention”, paragraph 17). Seward teaches the addition of a neurolytic (ethanol) to a blank hydrogel as discussed above. This neuromodulating agent is injected and, in one embodiment, is suspended in a self-assembling hydrogel (paragraph 51). Seward teaches these hydrogels have a “capacity for self-assembly” and trap the active agent in the matrix as the hydrogel assembles “due to contact with physiologic conditions”. This supports the conclusion that the hydrogel disclosed in Seward is an in situ forming gel. Additionally, this hydrogel is initially considered “blank” prior to the addition of additives such as phenol or ethanol as it contains no active ingredients prior to use.
Seward teaches the porosity of the hydrogel is 1-300 nm, which meets the instant limitations of less than about 20 microns (20,000 nm).
Seward is silent regarding the hydrogel being one which is linked through chemical crosslinking.
Nevertheless, it would have been obvious to one of ordinary skill in the art at the time of filing to utilize heparin/hyaluronic acid-PEG hydrogels, which are inherently neutral or negatively charged polymers, that are chemically crosslinked. The evidentiary art, Zare et al. (in PTO-892 filed 02/28/2024) discloses that “heparin is a negatively charged polysaccharide with various chain lengths and a hydrophilic backbone”, see Abstract. This evidentiary art shows that the claim limitations of claim 84 wherein the cross-linked gel is neutral or negatively charged are already being met by the heparin teaching. The method of Seward teaches hydrogels to deliver the drug (neurolytic). Cai is also concerned with using hydrogels to deliver drugs. Cai teaches that synthetic hydrogels may be created from heparin, hyaluronan (i.e., hyaluronic acid) and PEG-DA. This creates a “multivalent biomaterial capable of controlled release” of the drug of interest (abstract). While Cai used such a hydrogel for delivery of bFGF, one of ordinary skill in the art at the time of filing would have found it obvious that the synthetic ECM was not limited to delivery of that specific drug, but could have predictably been used to deliver other drugs, e.g., the neurolytic of Seward.
Like both Seward and Cai, Tan teaches hydrogels as useful for drug delivery systems (abstract). Tan teaches in situ forming hydrogels (p.1748) and that one way of doing this is through chemical crosslinking (section 3.2). Tan teaches that PEG-DA may be crosslinked in situ to form covalent crosslinked bonds (p.1754). Tan also teaches that HA gelates via chemical means including thermal, chemical, Schiff-base, Michael-type addition, and free radical crosslinking (table 1), which are forms of chemical crosslinking. Tan also teaches the benefits of choosing covalently crosslinked hydrogels over physical crosslinking (p.1751 section 3), motivating one of ordinary skill in the art to select covalent crosslinked polymers. Tan teaches “in situ cross linkable hydrogels based on thiol-modified hyaluronic acid satisfy many of the design criteria for in vitro and in vivo tissue engineering” (p.1754).
As noted by the United States Supreme Court, if a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability. For the same reason, if a technique has been used to improve one method (e.g., Cai’s method of drug delivery using HA-PEG hydrogels; Tan’s teaching of the benefits of using chemically crosslinked HA in situ), and a person of ordinary skill would recognize that it would improve similar methods (e.g., Seward’s method of drug delivery using hydrogels) in the same way, using the technique is obvious unless its actual application is beyond his or her skill. KSR, 127 S. Ct. at 1740. "When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product is not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show it was obvious under 35 U .S.C. 103." KSR Int'l Co. v. Teleflex Inc., 127 S.Ct. 1727, 1742, 82USPQ2d 1385, 1396 (2007).
Further, it is noted that the hydrogels of Cai are a combination of two or more precursor solutions (section 2.4) with an added crosslinker (p.6056 C2: “following addition of the crosslinker”) while Tan also teaches this strategy (e.g., mixing PEGDA and PEGMA, p.1754). This supports the conclusion that this hydrogel meets the instant limitations of a crosslinking gel and Seward/Tan provides the guidance to form hydrogels in situ.
Seward does not explicitly teach that the gel will maintain its integrity for 2 weeks-1 year.
However, Seward does teach that purpose of the hydrogel is to extend the activity of the agent in the target tissue “in the range of weeks to months or even years”, i.e., at least 2 weeks (“weeks”) to at least 2 years (“years”). In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP §2144.05(I). Further, this teaching would have made it obvious to one of ordinary skill in the art that the hydrogel is meant to persist at the flow site and allow the therapeutic (e.g., ethanol) to “slowly diffuse through the porous structure” (paragraph 51), motivating one of ordinary skill in the art to optimize the known result-effective variable of retention/integrity time. Finally, Seward teaches it is a property of a hydrogel that it will be “slowly resorbed by the surrounding tissue” (paragraph 51), meeting the instant limitations of “be degraded or resorbed following the period of time”.
With respect to the instant preamble (inhibiting nerve regeneration) as well as “inhibiting nerve regeneration of the target nerve with the cross-linked gel”, Seward does not disclose this outcome. However, the method of Seward meets all of the active method steps instantly claimed, including administering a neurolytic for an extended period of time in contact with a nerve to achieve denervation/sympathectomy. Applicant's attention is directed to MPEP § 2112 (II), which states, "there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003)." Furthermore, Integra Life Sciences I Ltd. v. Merck KGaA, 50 USPQ2d 1846 (DC SCalif, 1999) makes clear that a reference teaching a process may anticipate claims drawn to a method comprising the same process steps, despite the recitation of a different intended use in the preamble or the later discovery of a particular property of one of the starting materials or end products.
In this case, the discovery of another outcome of practicing the method of Seward as modified by Cai and Tan (inhibiting nerve regeneration) is insufficient to outweigh the conclusion of obviousness.
Regarding claim 85, the gel of the combined references is a cross-linked hydrogel as discussed above.
Regarding claim 93, Seward teaches injecting the hydrogel, supporting the conclusion that the hydrogel is injectable.
Regarding claim 94, as noted by the instant specification, shear-thinning is an inherent property of hyaluronic acid (paragraph 325) and therefore the inclusion of HA meets the limitations of “wherein the gel is shear-thinning.
Regarding claim 95, the solution of Seward have a “capacity” for self-assembly, but do not self-assemble until administered, e.g., paragraph 52: “in the presence of physiological conditions”. Thus, Seward teaches flowing a gel precursor (the unassembled hydrogel components), which are configured to transition from a precursor to the cross-linked gel. Further, the use of PEG-DA with HA for in situ formation of the hydrogel is discussed above.
Regarding claims 96 and 97, this is merely a property of fluids, e.g., a fluid will contour to the space it is in. This is supported by the instant specification paragraph 305, which notes that in situ forming materials (the hydrogel of Seward/Cai/Tan is such a material) can be injected through a fine needle (also taught by Seward) to form a solid that matches the contours of the potential space. Thus, when delivered to a targeted region, the gel will form a physical barrier at the targeted nerve.
Regarding claim 98, once the hydrogel forms in situ, there is now physical material in the space in which the target nerve might regenerate into and the hydrogel serves as a physical barrier to inhibit nerve regeneration as required in claim 98. Further, this hydrogel comprises ethanol, which will inhibit regeneration as described above. Absent evidence to the contrary, this constitutes a “physical barrier to the target nerve with the cross-linked gel”. This reads on the limitations of claim 98 wherein the hydrogel is used as a physical barrier to inhibit nerve regeneration.
Regarding claim 102, the crosslinking is covalent as described above.
Therefore, claims 84, 85, 93-98, and 102 would have been obvious.

Claims 84-89, 93-98, and 102 are rejected under 35 U.S.C. 103 as being unpatentable over Seward (US 20110104061; IDS 2/9/18 citation 24) in view of Cai and further in view of Tan and Bennett A (US 20120049689; in PTO-892 filed 11/20/2020).
Seward, Cai, and Tan are discussed above. Briefly, one of ordinary skill in the art at the time of filing would have found modifying the denervation method of Seward to include hyaluronic acid and PEG-DA for in situ hydrogel forming via covalent crosslinking and neurolytic delivery obvious.
Further, at the time of filing, one of ordinary skill in the art would have been aware of the various means and variables of preparing such hydrogels. In particular, Bennett A is also concerned with hydrogels for drug delivery (paragraph 104, 139). Bennett A also teaches the formation of such hydrogels in situ (paragraph 5) as well as teaches degradation rate is a result-effective variable (paragraph 66) and may be tuned to degrade over days, weeks, or months (paragraphs 67-68). Bennett A teaches including components such as hyaluronic acid (paragraph 81) and PEG-diacrylate (PEG-DA; paragraph 155). Bennett A teaches these hydrogels are formed from precursor components (paragraph 3) and are crosslinking (paragraph 5). Bennett A also teaches this hydrogel contours to the space, including by flow through a needle prior to transition to the cross-linked gel (paragraph 5 “adhering to the lumen”; figure 6).
Bennett A also teaches that the PEG may be multi-armed PEG in order to increase the functionalization groups, including having six or eight arms (paragraph 52). Such multi-armed PEG units are star-shaped (instant claim 86), comprises polyethylene glycol (instant claim 87), is multi-armed (instant claim 88), and comprises PEG of at least 6-arms (instant claim 89).
Therefore, claims 84-89, 93-98, and 102 would have been obvious.

Response to Arguments
Applicant's arguments filed 02/11/2025 have been fully considered but they are not persuasive.
Applicant argues that the references fail to teach, individually or in combination, a method of inhibiting nerve regeneration comprising the use of an in-situ cross-linking blank gel. Applicant argues that the combination of references “teach away” from the instant invention’s goal of providing a stable barrier to neurite outgrowth during the initial phase when axonal sprouting in response to injury is maximal. This is not found persuasive.
In response to applicant's arguments against the references individually, 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). Additionally, a person of ordinary skill in the art would have been motivated to combine treatment modalities known to be useful for the same conditions, and would have expected the combination therapy to be at least as good as either therapy alone (see MPEP §2144.06)
Applicant argues that Seward discloses the use of a peptide hydrogel matrix for the delivery of neuromodulating agents, which would encourage attachment and outgrowth of neuronal cells and features that would not be suitable for providing a physical barrier to nerve regeneration. This is not persuasive because Seward also discloses teaches methods of neuromodulation, specifically denervation/sympathectomy (see paragraph 19). Seward teaches that one means of inhibiting the relevant nerves/neurons is by administering ethanol (“phenol and ethanol have also been used to produce chemical sympathectomy and are also useful in the methods of this invention”, paragraph 17). Seward teaches the hydrogel containing a neurolytic (ethanol) as discussed above. The addition of the ethanol would serve to inhibit nerve regeneration, and not encourage growth as Applicant is stating.
Applicant argues that Cai discloses the use of “covalently linked, heparin-containing glycosaminoglycan hydrogels” as “promising new materials for controlled release of heparin-binding growth factors in vivo” which results in increased neovascularization. In the context of the rejection, Cai was brought in to teach how hydrogels are capable of delivering drugs and is not limited to only the specific drug embodiment of fibroblast growth taught in the prior art. Because the prior art teaches the release of basic fibroblast growth due to the drug used in the embodiment, the increased neovascularization are limited to the specific drug as a property of such. Therefore, if that particular drug is not used, one skilled in the art would reasonably expect to not experience neovascularization when administering a drug that does not have those characteristics. One of ordinary skill in the art would recognize that the delivery method of hydrogels disclosed in Cai are interchangeable, wherein one could replace the growth factor with a number of other elements catered towards the preferred final result.
Applicant argues that Tan only discusses soft tissue regeneration after tumor removal or trauma and controlled drug delivery and thus, teaches away from the use of a blank hydrogel to inhibiting nerve regeneration. In the context of the instant rejection, Tan is not relied upon to treat particular diseases; rather, it is relied upon to teach cross linkable hydrogels that are used in drug delivery systems for a broad range of methods of tissue engineering for a variety of functions. Tan was incorporated in the rejection to teach a technique that can be used to improve one method (e.g., Cai’s method of drug delivery using HA-PEG hydrogels; Tan’s teaching of the benefits of using chemically crosslinked HA in situ), and a person of ordinary skill would recognize that it would improve similar methods (e.g., Seward’s method of drug delivery using hydrogels) in the same way, using the technique is obvious unless its actual application is beyond his or her skill. KSR, 127 S. Ct. at 1740. "When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product is not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show it was obvious under 35 U .S.C. 103." KSR Int'l Co. v. Teleflex Inc., 127 S.Ct. 1727, 1742, 82USPQ2d 1385, 1396 (2007).
Further, it is noted that the hydrogels of Cai are a combination of two or more precursor solutions (section 2.4) with an added crosslinker (p.6056 C2: “following addition of the crosslinker”) while Tan also teaches this strategy (e.g., mixing PEGDA and PEGMA, p.1754). This supports the conclusion that this hydrogel meets the instant limitations of a crosslinking gel and Seward/Tan provides the guidance to form hydrogels in situ.
Applicant argues that the claim amendments to recite “blank gels” is sufficient to overcome the rejections on record. However, this amendment is not sufficient to overcome the prior art references as all inventions in the same field of endeavor also begin with blank gels and rely on the addition of targeted agents to arrive at their preferred embodiments. These factors are optimized towards a preferred result, just as the disclosure of the instant invention does with the addition of hydrogels, polymers, and other additives.
This argument regarding the amendment to a “blank gel” is not persuasive because optimization of a hydrogel to target a certain cellular process, such as nerve regeneration, is considered routine and conventional within the art, and the argument that modification of the gel renders the instant invention distinct from the gel(s) of the prior art is not persuasive for nonobviousness. It would have been obvious to the ordinary artisan to modify the composition to inhibit nerve regeneration because it was already known than such changes could be advantageous when preparing hydrogels for such functions. One of ordinary skill in the art would argue that the inhibitor function observed after modification and optimization of the composition was expected, especially in the view of the art recognized need to develop deliverable hydrogels with inhibitory characteristics and to modify the composition to provide the best result for a specific function through routine optimization. Modifying the composition to reach this endpoint is a part of routine optimization.
Therefore, the rejections are maintained.

Conclusion
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.
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675