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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-2, and 6-11, and the species of N-succinyl-[Glu9, Ala 11,15] endothelin 1 (sovateltide, IRL-1620), brain-derived neurotrophic factor, and glycerol in the reply filed on 6/9/2025 is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) were submitted on 7/11/2024 and 7/17/2025 before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-11, filed 11/6/2025, are pending. Claims 1-2 and 6-11 are under examination. Claims 3-5 are currently withdrawn.
Claim Interpretation
The phrase “includes” in claim 1 has been interpreted to be equivalent to “comprises” because MPEP 2111.03(I) states: “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) “.
Claim Objections
Previous Objections
Claim 11 was previously objected to because of the following informalities: the phrase “wherein endothelin analog dose is” is better written as “wherein the endothelin analog is administered in a dose range of…”. Appropriate correction is required.
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 5, para. 3, filed 11/6/2025, with respect to claim 11 have been fully considered and are persuasive. The objection to claim 11 has been withdrawn.
New Objections
Claim 2 is objected to because of the following informalities. Claim 2 recites “… wherein the endothelin analog is an endothelin B receptor analogs…” One part of this phrase is singular and the other is plural. Appropriate correction is required.
Claim 7 is objected to because of the following informalities. Amended claim 7 recites “The method of claim 1, wherein the endothelin analogs are in the form or conjugated with nanoparticles..”. The phrase “in the form” should be followed by the preposition “of” to be in agreement with the phrase “conjugated with”. Appropriate correction is required.
Claim 10 is objected to because of the following informalities. The phrase “endothelin analogs administration” is better written as “the administration of the endothelin analogs”. Appropriate correction is required.
Claim 11 is objected to because of the following informalities. Claim 11 recites “in a dose range is 0.00001…”. This should be changed to “in a dose range of 0.00001…” 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.
Previous Rejections
Claims 1-2 and 6-11 were previously 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.
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 5, para. 8, filed 11/6/2025, with respect to the rejection of claims 1-2 and 6-11 under 35 U.S.C 112(b) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, new grounds of rejection are made.
New Rejections
Claims 1, 2 and 7-11 are 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.
Regarding claim 1, claim 1 recites: “…by the mechanism of anti-apoptotic, anti-inflammatory, and anti-oxidant activity that limits the death of cells and promotes the formation of new neurons (neurogenesis) and new blood vessels (angiogenesis) enhancing the healing of wounds and regenerating nerves.”
It is not clear whether the blood vessels are enhancing the healing of wounds and regenerating nerves or the mechanism as a whole is enhancing the healing of wounds and regeneration nerves. Clarification is required.
Also, based off the disclosure of the specification, it is not clear whether “endothelin analogs” should be plural because the only endothelin analog used is IRL-1620. It is not clear what the other endothelin analogs claim 1 would be referencing.
Claim 1 is rejected.
Claim 2 recites the limitation "the endothelin analog" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 recites “endothelin analogs” and it is not also not clear to which endothelin analog claim 2 refers.
Claim 2 is rejected.
Regarding claim 7, the phrase "including" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. Claim 7 also includes the phrase “such as”. See MPEP § 2173.05(d).
Claim 7 also includes “various formulations”. It is not clear which formulations are included in this term. Clarification is required.
Finally, it is not clear whether there are two or three elements after the phrase “are in the form or conjugated with”. The elements could be nanoparticles, hydrogels, and sprays or the elements could just be nanoparticles and hydrogels. If the elements only include nanoparticles and hydrogels, the claims should include an “or” to make this clear.
Consequently, claim 7 is rejected.
Regarding claim 8, the phrase "may be" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(h): “If a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group "comprising" or "consisting essentially of" the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b).”
In claim 8, the phrase “may be” creates an open ended Markush group, and therefore is rejected.
Claim 8 also recites “sustained release is Lipid core nanocapsules poly L-lysine (HBPL) nanoparticles”. This phrase is part of a Markush group of drug delivery systems. In this case, “sustained release is” should be omitted. Also, it is not clear what is meant by “Lipid core”. This could be a tradename. Or, Lipid core nanocapsules may be different than poly L-lysine nanoparticles. Clarification of these elements or this element is required.
Claim 8 is rejected.
Regarding claim 9, claim 9 recites “… are used for the treatment of wounds and or promoting wound healing and for mammalian nerve regeneration of a damaged nerve.” If this is meant to be three elements, “and or” should be removed and commas placed after “wounds” and “healing”. Additionally, if these are meant in the alternative, “… and for mammalian nerve regeneration of a damaged nerve” should start with “or” not “and”.
Claim 9 is rejected.
Regarding claim 10, , the phrase "may include" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Also, the phrase "may be" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). This is used twice in the claim: “The method of claim 1, wherein endothelin analogs administration may be…” and “wherein the osmotic agent may be glycerol”.
Claim 10 is rejected.
Regarding claim 11, the phrase "may be" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 11 also recites the limitation "the endothelin analog" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 recites “endothelin analogs” and it is not also not clear to which endothelin analog claim 11 refers.
Claim 11 is rejected.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Previous Rejections
Claims 1-2 and 6-11 were previously rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for relieving or reversing a wound, ameliorating a symptom of a wound, accelerating epithelialization, and increasing wound breaking strength, does not reasonably provide enablement for wound prevention from occurring. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
MPEP 2164.01(a) states: “In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is ‘reasonable’ or is ‘undue.’”
These factors include, but are not limited to:
The breadth of the claims;
Claim 1 is fairly broad with respect to term “treating” as defined in the specification: “As used herein, the term "treating" or "treatment" includes preventing a disease,
disorder, or condition from occurring in a subject predisposed to or having a disease, disorder and/or condition; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving or reversing the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating a disease or condition may also include ameliorating at least one symptom of the particular disease or condition.”
The nature of the invention;
The invention is a method for treating dermal or cutaneous wounds and damaged cranial or peripheral nerves using a compound that includes endothelin analogs by the mechanism of anti-apoptotic, anti-inflammatory, and anti-oxidant activity that limits the death of cells and promotes the formation of new neurons (neurogenesis) and new blood vessels (angiogenesis) enhancing the healing of wounds and regenerating nerves.
The state of the prior art;
Endothelin is a well-studied and well-known peptide family. Barton (Barton, et al. Hypertension 74.6:1232-1265 (2019)) and Masaki (Masaki, Trends in Pharmacological Sciences 25.4: 219-224 (2004)) describe endothelin and the primary members of the family: endothelin 1, endothelin 2, and endothelin 3.
The level of one of ordinary skill;
One of ordinary skill in the art is high; typically a master’s level education or higher.
The level of predictability in the art;
The predictability for peptides is low in general due to factors such as effects from point mutations and aggregation as described by Bolognesi (Bolognesi, et al. ACS Chemical Biology 9.2: 378-382. (2014)), Sawai (Sawai, et al. Protein engineering 15.3: 225-232. (2002)), and Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)).
The amount of direction provided by the inventor and the existence of working examples; and The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The production and administration of the disclosed peptides are well-known in the art. The present specification discloses evidence of relieving or reversing a wound, ameliorating a symptom of a wound, accelerating epithelialization, and increasing wound breaking strength. However, nothing reduced to practice shows efficacy in preventing wounds, nor is any mechanism suggested for such an effect in the specification.
Response to Arguments
Applicant's arguments filed see Applicant Reply, page 6, para. 3, filed 11/6/2025 have been fully considered but they are not persuasive. Additionally, new grounds of rejection are made.
Regarding claim 1, claim 1 recites: “A method for therapeutically treating dermal or cutaneous wounds and damaged cranial or peripheral nerves using endothelin analogs by the mechanism of anti-apoptotic, anti-inflammatory, and anti-oxidant activity that limits the death of cells and promotes the formation of new neurons (neurogenesis) and new blood vessels (angiogenesis) enhancing the healing of wounds and regenerating nerves.”
As described above, the term “treating” encompasses prevention as recited in paragraph [0085] of the specification. The present specification discloses evidence of relieving or reversing a wound, ameliorating a symptom of a wound, accelerating epithelialization, and increasing wound breaking strength. However, nothing reduced to practice shows efficacy in preventing wounds, nor is any mechanism suggested for such an effect in the specification. Consequently, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with claim 1. Claim 1 is rejected.
Applicant has amended claim 1 to recite “therapeutically”. However, no special definition of term “therapeutically” is present in the specification. Therefore, the broadest reasonable interpretation is invoked. A therapeutic method, in the broad sense, is any method used for therapy of an injury or disease state.
Consequently, a method for “therapeutically treating” is still mainly defined by the term “treating”. As recited by the specification in paragraph [00085], “treating” includes preventing a disease, disorder, or condition. Amended claim 1 uses the term “treating”, and therefore, prevention is within the scope of claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The rejection of claim 1 under U.S.C. 112(a) is maintained.
Regarding claim 2, claim 1 is rejected as described above. Claim 2 does not provide any additional information that enables any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with claim 1. Therefore, the rejection of claim 2 is also maintained.
Regarding claims 6-11, claim 1 is rejected as described above. Claims 6-11 do not provide any additional information that enables any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with claim 1. Therefore, claims 9-11 are also rejected.
New Rejections
Claims 1 and 6-11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for analogs N-Succinyl-[Glu9, Ala1',15] endothelin 1 (sovateltide, IRL-1620), BQ-3020, [Ala1,3,11,15]-endothelin, sarafotoxin S6c, and endothelin 3, does not reasonably provide enablement for any possible endothelin analog. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
MPEP 2164.01(a) states: “In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is ‘reasonable’ or is ‘undue.’”
These factors include, but are not limited to:
The breadth of the claims;
Claim 1 is very broad with respect to endothelin analogs; any possible endothelin analog is claimed.
The nature of the invention;
The invention is a method for treating dermal or cutaneous wounds and damaged cranial or peripheral nerves using a compound that includes endothelin analogs by the mechanism of anti-apoptotic, anti-inflammatory, and anti-oxidant activity that limits the death of cells and promotes the formation of new neurons (neurogenesis) and new blood vessels (angiogenesis) enhancing the healing of wounds and regenerating nerves.
The state of the prior art;
Endothelin agonists are well known in the art. Cody et al. (Cody, et al. Biopolymers: Original Research on Biomolecules 37.2: 89-104 (1995)) discloses several endothelin agonists such as BQ-3020 and [Ala1,3,11,15]ET-1 (Cody et al., page 92, cols. 2-4). However, Cody et al. also discloses that not all endothelin agonists possess the necessary activity to carry out the claimed method: “The C-terminal hexapeptide of endothelin itself has been reported to possess very weak binding affinity at both receptor subtypes (50-100 μM). Functionally, the C-terminal hexapeptide was an agonist in the guinea pig bronchus, the rabbit pulmonary artery, and the rat vas deferens, but was completely devoid of activity in the guinea pig ileum, rat aorta, human renal pelvis/artery, and human urinary bladder. Interestingly, even though ET- 1 (His16-Leu-Asp-Ile-Ile-Trp21)had significant agonist activity in the guinea pig bronchus, ET-I( 17-2 1) had 100-fold less activity, and SRTX(16-21), which has two conservative substitutions (Gln17for Leu17and ValI9 for Leu19) had 1000-fold less activity. In addition, ET- 1( 16-21) amide was found to be completely inactive in all tissues examined.”
The level of one of ordinary skill;
One of ordinary skill in the art is high; typically a master’s level education or higher.
The level of predictability in the art;
The predictability for peptides is low in general due to factors such as effects from point mutations and aggregation as described by Bolognesi (Bolognesi, et al. ACS Chemical Biology 9.2: 378-382. (2014)), Sawai (Sawai, et al. Protein engineering 15.3: 225-232. (2002)), and Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)).
The amount of direction provided by the inventor and the existence of working examples; and The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Applicants disclose the activity for one endothelin agonist: IRL-1620.
Regarding claim 1, claim 1 recites a method for therapeutically treating dermal or cutaneous wounds and damaged cranial or peripheral nerves using endothelin analogs by the mechanism of anti-apoptotic, anti-inflammatory, and anti-oxidant activity that limits the death of cells and promotes the formation of new neurons (neurogenesis) and new blood vessels (angiogenesis) enhancing the healing of wounds and regenerating nerves.
The prior art shows that BQ-3020, [Ala1,3,11,15]-endothelin, sarafotoxin S6c, and endothelin 3 possess the desired activity, but as described above, all possible endothelin agonists do not possess the required activity. Claim 1 claims all possible endothelin agonists and this would require undue experimentation to determine which agonists possess the desired activity and which do not. Consequently, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and claim 1 is rejected.
Regarding claims 6-11, these claims have the same scope as claim 1 and therefore the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and claims 6-11 are rejected.
Claim 2 is fully supported by the specification and prior art disclosures and therefore not subject to this rejection.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Previous Rejections
Claims 1, 2, 6, 9, and 10 were previously rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gulati (Gulati et al. US 2016/0151450, published 6/2/2016).
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 6, para. 6, filed 11/6/2025 have been fully considered and are persuasive. The rejection of claims 1, 2, 6, 9, and 10 has been withdrawn.
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.
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.
Previous Rejections
Claims 7, 8, and 11 were previously rejected under 35 U.S.C. 103 as being unpatentable over Gulati (Gulati et al. US 2016/0151450, published 6/2/2016) in view of Davar (US 2004/0176274, published 9/9/2004).
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 6, para. 6, filed 11/6/2025 have been fully considered and are persuasive. The rejection of claims 1, 2, 6, 9, and 10 has been withdrawn. However, upon further consideration, a new ground of rejection is made as described below.
New Rejections
Claims 1, 2, 6, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Leonard et al. (Leonard, et al. Brain research 1528: 28-41 (2013)) in view of Lipa et al. (Lipa, et al. American Journal of Physiology-Heart and Circulatory Physiology 276.2: H359-H367 (1999)), Gulati et al. (Gulati et al. US 2016/0151450, published 6/2/2016), Detmar (Detmar, Michael. Journal of dermatological science 24: S78-S84 (2000)), Goligorksy et al. (Goligorsky, et al. Clinical and Experimental Pharmacology and Physiology 26.3: 269-271 (1999)), and Nour et al. (Nour, et al. Journal of Biomedical Materials Research Part A 109.4: 453-478. (2021)).
Leonard et al. discloses that endothelin-B analog IRL-1620 can promote angiogenesis in ischemic rats: “Whereas occluded animals treated with vehicle presented with an average of 1.17±0.46 VEGF-positive vessels per 30 µm slice, IRL-1620 treated animals presented with an average of 4.17±0.52 VEGF-positive vessels/30 µm slice (P<0.01) as early as 24 h post MCAO (Fig. 4C). This increase in angiogenesis remained evident up to 1 week following MCAO, with significantly more VEGF-positive blood vessels in the group treated with IRL-1620 versus vehicle (11.33±2.13 and 4.19±0.79 VEGF-positive vessels/30 µm slice, respectively; P<0.0001).” (Leonard et al., page 31, col. 2, para. 3).
Leonard also discloses that neurogenesis can accompany the angiogenesis described above: “Our results also indicate that, in addition to enhanced angiogenesis, selective stimulation of ETB receptors leads to increased neurogenesis following cerebral ischemia.” (Leonard et al., page 37, col. 1, para. 1).
Leonard does not specifically disclose the usage of endothelin-B analogs in dermal or cutaneous wounds. However, Lipa discloses that human skin possesses ETA and ETB receptors: “Of particular interest to us is the relative functional importance of ETA and ETB receptors in the mediation of vasoconstriction in human skin.” (Lipa et al., page H359, col. 2, para. 2).
Furthermore, Gulati discloses how endothelin agonists can induce production of VEGF in neurons, astrocytes, and endothelial cells: “ VEGF is an endogenous protein known for its ability to promote angiogenesis and enhance vascular permeability. Under hypoxic conditions such as cerebral ischemia, VEGF expression is induced in neurons, astrocytes and endothelial cells via hypoxia-inducible factor-1 (HIF-1) (Breier and Risau, 1996). Once expressed, VEGF initiates both direct and indirect neuroprotective actions, inhibiting apoptosis, stimulating neurogenesis and angiogenesis, increasing glucose uptake and activating antioxidants (Gora-Kupilas and Josko, 2005). It has been shown that intracerebroventricular (i.c.v.) administration of an ETB receptor agonist in normal rats stimulates production of VEGF and activates VEGF receptors in the brain, while, in cultured astrocytes, this agonist increases VEGF-A mRNA as well as BrdU incorporation (Koyama et al., 2012; Koyama et al., 2011). “ (Gulati et al. para [0109].
Also, Detmar discloses that hypoxia conditions in skin can lead to VEGF upregulation, just like in the neuronal case disclosed by Gulati: “(2) Skin hypoxia directly leads to upregulation
of VEGF expression by epidermal keratinocytes, dermal fibroblasts and dermal endothelial cells [12]. Hypoxia also induces upregulation of the VEGF receptor Flt1:VEGFR-1 on microvessels, suggesting the existence of an autocrine pro-angiogenic loop.” (Detmar, page S81, col. 1, para. 1).
Goligorsky discloses that ETB receptor agonism can accelerate healing in endothelial cells through an NO intermediate: “Through application of specific agonists and antagonists of known endothelin receptors, it was possible to implicate ETB receptors in the observed responses. However, these effects of ET were mediated by endogenous NO production, as asserted to by the results of three independent experimental approaches. In the first series of experiments, L-NAME prevented ET-1-induced endothelial cell transwell migration. In the second, CHO-ETBNOS cells, a model cell system devoid of complexity inherent to endothelial cells, showed NO dependency of migration induced by ET-1. Finally, application of eNOS isoform-selective antisense S-ODN, but not sense or scrambled constructs, to endothelial cells suppressed their migratory responsiveness to ET-1. Therefore, stimulated NO production serves a permissive role in ET-induced acceleration of endothelial cell motility and wound healing.” (Goligorsky et al., page 271, col. 1, para. 2)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the endothelin analog of Leonard in a dermal or cutaneous wound as disclosed by Lipa and Detmar to achieve the VEGF upregulation and other benefits as disclosed by Gulati.
A person of ordinary skill in the art would be motivated to use the endothelin analog of Leonard in this way to achieve the angiogenic and neurogenic benefits of VEGF upregulation as disclosed by Gulati in a dermal setting where angiogenesis and neurogenesis can be useful for wound repair as disclosed by Nour: “Angiogenesis is a key factor in the healing process and tissue regeneration and impaired angiogenic response results in several healing disorders which can be observed for example in diabetic foot ulcers and nonunion bone fractures. Regarding the oxygen requiring nature of the cells and the prolonged hypoxic condition in severe and full-thickness wounds, angiogenic induction approaches can recruit healing promoting cells to restore both the normal structure and function of the damaged skin.” (Nour et al., page 453, Introduction).
A person of ordinary skill in the art would have a reasonable expectation of success because the claimed endothelin analogs would be working on the same ETA and ETB receptors in the dermal region that they agonize in brain tissue as disclosed by Gulati. Lipa discloses that the skin region has both ETA and ETB receptors. Therefore, it is a reasonable expectation that the endothelin agonists will upregulate VEGF as disclosed by Gulati except in the dermal region. Furthermore, Goligorsky discloses that ETB receptor agonism can accelerate healing in endothelial cells through an NO intermediate.
As discussed by Detmar, the skin region will respond to hypoxic conditions with upregulation of VEGF to promote angiogenesis. Therefore, there is a reasonable expectation that upregulation of VEGF through ETB agonism will provide the angiogenic response discloed by Detmar and Gulati and the neurogenic response disclosed by Gulati.
Regarding the recited mechanisms, Gulati discloses that: “Additionally, studies demonstrate that ETB receptor activation enhanced proliferation of neurons and inhibit apoptosis.” (Gulati et al., para. [0110]). Gulati also discloses: “Once expressed, VEGF initiates both direct and indirect neuroprotective actions, inhibiting apoptosis, stimulating neurogenesis and angiogenesis, increasing glucose uptake and activating antioxidants (Gora-Kupilas and Josko, 2005).” (Gulati et al., para. [0109]).
Consequently, claim 1 is obvious over Leonard et al. in view of Lipa et al., Gulati et al., Goligorksy et al., and Nour et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites: “The method of claim 1, wherein endothelin B receptor analogs are selected from the group consisting of N-Succinyl-[Glu9, Ala11,15 endothelin 1 (sovateltide, IRL-1620), BQ-3020, [Ala1,3,11,15]-endothelin, sarafotoxin S6c, and endothelin 3.” Gulati discloses: “More specifically, the present invention provides for use of IRL-1620, an endothelin-B receptor agonist, in appropriate doses to be a neuroprotective and a neuroregenerative agent.” (Gulati et al., para [0019]). Consequently, claim 2 is obvious over Leonard et al. in view of Lipa et al., Gulati et al., Goligorksy et al. (Goligorsky, et al., and Nour et al. and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites the case where endothelin B receptor analogs are delivered topically, sub- dermally, subcutaneously, intramuscularly, intravenously, or orally. Gulati discloses: “It has been demonstrated that activation of ETB receptors with intravenous IRL-1620, a highly selective ETB agonist, results in a significant elevation in CBF in normal rats and reduction in neurological deficit and infarct volume of stroked rats (Leonard et al., 2011; Leonard and Gulati, 2009).” (Gulati et al., para [0012]). Consequently, claim 6 is obvious over Leonard et al. in view of Lipa et al., Gulati et al., Goligorksy et al., Detmar et al., and Nour et al. and rejected.
Regarding claim 11, claim 11 further recites the case endothelin analog dose range is 0.00001 to about 1 mg and may be administered once or multiple times in a day, weeks. or months. Gulati discloses: “In some embodiments, the endothelin-B receptor agonist is administered at a dose ranging from 0.0001 to 0.5 mg/kg.” (Gulati para. [0024]). The range of claim 11 is not given on a per weight basis. However, for a 100 kg person, the range becomes 0.0000001 to about 0.01 mg. This range overlaps with the range disclosed by Gulati. MPEP 2144.05(I) recites: “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) “. Consequently, claim 11 is obvious over Leonard et al. in view of Lipa et al., Gulati et al., Goligorksy et al., Detmar et al., and Nour et al. and rejected.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Leonard et al. (Leonard, et al. Brain research 1528: 28-41 (2013)) in view of Lipa et al. (Lipa, et al. American Journal of Physiology-Heart and Circulatory Physiology 276.2: H359-H367 (1999)), Gulati et al. (Gulati et al. US 2016/0151450, published 6/2/2016), Detmar (Detmar, Michael. Journal of dermatological science 24: S78-S84 (2000)), Goligorksy et al. (Goligorsky, et al. Clinical and Experimental Pharmacology and Physiology 26.3: 269-271 (1999)), and Nour et al. (Nour, et al. Journal of Biomedical Materials Research Part A 109.4: 453-478. (2021)) as applied to claim 1 above, further in view of Fam et al. (Fam, et al. Nanomaterials 10.4: 787. (2020)).
Regarding claim 7, claim 1 is obvious as described above. Leonard et al., Lipa et al., Gulati et al., Goligorksy et al., and Nour et al. do not specifically disclose the case where endothelin B receptor analogs are conjugated with nanoparticles including stealth nanoparticles, hydrogels made into various formulations such as gels, creams, solutions, lotions, ointments, adhesive patches, and sprays.
However, Fam discloses that peptides may be conjugated to nanoparticles to enhance drug delivery: “Nanoparticles (NPs) have emerged as a powerful drug-delivery tool for cancer therapies to enhance the specificity of drug actions, while reducing the systemic side effects. Nonetheless, NPs interact massively with the surrounding physiological environments including plasma proteins upon administration into the bloodstream. Consequently, they are rapidly cleared from the blood circulation by the mononuclear phagocyte system (MPS) or complement system, resulting in a premature elimination that will cause the drug release at off-target sites. By grafting a stealth coating layer onto the surface of NPs, the blood circulation half-life of nanomaterials can be improved by escaping the recognition and clearance of the immune system.” (Fam et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to conjugate the endothelin agonist of Leonard et al., Lipa et al., Gulati et al., Goligorksy et al., Detmar et al. and Nour et al. to the nanoparticle of Fam et al. A person of ordinary skill in the art would be motivated to do this to achieve the benefits disclose by Fam above such as reducing side effects and enhancing specificity. A person of ordinary skill in the art would have a reasonable expectation of success because Fam discloses that nanoparticles are now a common vehicle for peptide drug delivery: “Over the past few decades, nanotechnology has contributed tremendously to the advance and development of nanoscale materials and nanoparticles (NPs) for various biomedical applications. NPs have received considerable interest in the delivery of therapeutic agents owing to their unique features of large surface-to-volume ratio with a greater capacity for drug loading and high functionalization possibilities.” (Fam et al., page 2, para. 1).
Consequently, claim 7 is obvious over Leonard et al. in view of Lipa et al., Gulati et al., Goligorksy et al., Detmar et al., and Nour et al. and further in view of Fam et al. and rejected.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Leonard et al. (Leonard, et al. Brain research 1528: 28-41 (2013)) in view of Lipa et al. (Lipa, et al. American Journal of Physiology-Heart and Circulatory Physiology 276.2: H359-H367 (1999)), Gulati et al. (Gulati et al. US 2016/0151450, published 6/2/2016), Detmar (Detmar, Michael. Journal of dermatological science 24: S78-S84 (2000)), Goligorksy et al. (Goligorsky, et al. Clinical and Experimental Pharmacology and Physiology 26.3: 269-271 (1999)), and Nour et al. (Nour, et al. Journal of Biomedical Materials Research Part A 109.4: 453-478. (2021)) as applied to claim 1 above, further in view of Young et al. (Young, Simon, et al. Journal of controlled release 109.1-3: 256-274. (2005)).
Regarding claim 8, claim 1 is obvious as described above. Leonard et al., Lipa et al., Gulati et al., Goligorksy et al., Detmar et al., and Nour et al. do not specifically disclose the case where endothelin B receptor analogs are administered via a sustained release drug delivery system.
However, Young discloses the usage of gelatin for sustained drug release: “In order to address this issue, mild formulation conditions have been used to fabricate a multitude of polymer hydrogels as matrices for protein release, with the intent of maintaining the bioactivity of a protein drug during production. By incorporating the protein within an inert polymer delivery vehicle, the therapeutic agent is protected against enzymatic degradation and immunologic neutralization in vivo, thus allowing for prolonged release of the protein.” (Young et al., page 258, col. 1, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the gelatin drug delivery system of Young in conjunction with the endothelin agonist of Leonard et al., Lipa et al., Gulati et al., Goligorksy et al., and Nour et al.
A person of ordinary skill in the art would be motivated to use the gelatin to achieve the benefits disclosed by Young above, such as protection from enzymatic degradation and immunologic neutralization.
A person of ordinary skill in the art would have a reasonable expectation of success because such gelation delivery method have been used in angiogenic treatments before: “With the results of these two studies demonstrating the effectiveness by which bFGF delivery from gelatin hydrogels was able to stimulate angiogenesis, numerous therapeutic applications using this technique have been studied [28], [48], [49], [50], [51]. Sakakibara et al. [50] investigated the use of gelatin microspheres loaded with bFGF to induce coronary collateral growth, a novel technique that shows promise for patients who are not candidates for standard revascularization procedures such as coronary angioplasty, or coronary artery bypass graft surgery.” (Young et al., page 268, col. 2, para. 2).
Consequently, claim 8 is obvious over Leonard et al. in view of Lipa et al., Gulati et al., Goligorksy et al., and Nour et al. Detmar et al., and further in view of Young et al. and rejected.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Leonard et al. (Leonard, et al. Brain research 1528: 28-41 (2013)) in view of Lipa et al. (Lipa, et al. American Journal of Physiology-Heart and Circulatory Physiology 276.2: H359-H367 (1999)), Gulati et al. (Gulati et al. US 2016/0151450, published 6/2/2016), Detmar (Detmar, Michael. Journal of dermatological science 24: S78-S84 (2000)), Goligorksy et al. (Goligorsky, et al. Clinical and Experimental Pharmacology and Physiology 26.3: 269-271 (1999)), and Nour et al. (Nour, et al. Journal of Biomedical Materials Research Part A 109.4: 453-478. (2021)) as applied to claim 1 above, further in view of Bao et al. (Bao, Philip, et al. Journal of Surgical Research 153.2: 347-358. (2009)).
Regarding claim 9, claim 1 is obvious as described above. Claim 9 further recites the case where endothelin analogs are used for the treatment of wounds and/or promoting wound healing and for mammalian nerve regeneration of a damaged nerve.
Detmar discloses that the ETB induced upregulation of VEGF described is known to be useful for the healing of skin wounds: “This mechanism is likely important in the induction of epidermal VEGF expression during wound healing and in areas of skin cancers adjacent to tumor necroses.” (Detmar et al., page S81, col. 2, para. 1).
Furthermore, Bao et al. discloses that: “VEGF stimulates wound healing via multiple mechanisms including collagen deposition, angiogenesis, and epithelialization. In the clinical setting, the mitogenic, chemotactic, and permeability effects of VEGF may potentially aid in promoting repair in nonhealing wounds in arterial occlusive disease and diabetes. It may also alleviate the “wound” of ischemic heart disease. By promoting angiogenesis, VEGF improves tissue perfusion. Sustained release of VEGF (through adenovirus gene, biodegradable polymer, fibrin mesh, etc.) should be tested as rapidly as possible in patients with diabetic foot ulcers and pressure ulcers.” (Bao et al., page 354, col. 1, para. 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the endothelin agonist of Leonard et al., Lipa et al., Gulati et al., Goligorksy et al., Detmar et al., and Nour et al. to treat wounds as discussed by Detmar and Bao.
A person of ordinary skill in the art would be motivated to use the endothelin agonist to upregulate VEGF to achieve the benefits disclosed by Bao: “VEGF stimulates wound healing via multiple mechanisms including collagen deposition, angiogenesis, and epithelialization.” (Bao et al., page 354, col. 1, para. 4).
A person of ordinary skill in the art would have a reasonable expectation of success because VEGF is implicated in wound healing: “In summary, direct and indirect evidence implicates VEGF as a significant factor in wound healing immediately after injury. Induced by inflammatory cells and local wound conditions, VEGF potentially alleviates tissue hypoxia and metabolic deficiencies by promoting early events in angiogenesis, as well as endothelial cell function.” (Bao et al., page 352, col. 1, para. 3) and as discussed above, the endothelin agonists upregulate VEGF in the treated area.
Consequently, claim 9 is obvious over Leonard et al. in view of Lipa et al., Gulati et al., Goligorksy et al., Detmar et al. and Nour et al. and further in view of Bao et al. and rejected.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Leonard et al. (Leonard, et al. Brain research 1528: 28-41 (2013)) in view of Lipa et al. (Lipa, et al. American Journal of Physiology-Heart and Circulatory Physiology 276.2: H359-H367 (1999)), Gulati et al. (Gulati et al. US 2016/0151450, published 6/2/2016), Detmar (Detmar, Michael. Journal of dermatological science 24: S78-S84 (2000)), Goligorksy et al. (Goligorsky, et al. Clinical and Experimental Pharmacology and Physiology 26.3: 269-271 (1999)), and Nour et al. (Nour, et al. Journal of Biomedical Materials Research Part A 109.4: 453-478. (2021)) as applied to claim 1 above, further in view of Bathina et al. (Bathina, et al. Archives of medical science 11.6: 1164-1178.) (2015).
Regarding claim 10, claim 1 is obvious as described above. Claim 10 further recites the case where endothelin analogs may be combined with growth factors, osmotic agents, or both. Leonard et al., Lipa et al., Gulati et al., Goligorksy et al., Detmar et al., and Nour et al. do not specifically disclose the case where endothelin analogs may be combined with growth factors, osmotic agents, or both.
However, Bathina discloses that: “Brain-derived neurotrophic factor (BDNF) is one of the neurotrophic factors that support differentiation [1], maturation [2], and survival of neurons in the nervous system [3] and shows a neuroprotective effect under adverse conditions, such as glutamatergic stimulation, cerebral ischemia, hypoglycemia, and neurotoxicity [4]. BDNF stimulates and controls growth of new neurons from neural stem cells (neurogenesis) [5, 6], and BDNF protein and mRNA have been identified in most brain areas including the olfactory bulb, cortex, hippocampus, basal forebrain, mesencephalon, hypothalamus, brainstem and spinal cord. The levels of BDNF are decreased in many neurodegenerative diseases such as Parkinson’s disease (PD) [7], multiple sclerosis (MS) [8] and Huntington’s disease [9]. Besides the neuroprotective effect, BDNF plays a major role in energy homeostasis. The BDNF administration peripherally or intracerebroventricularly (ICV) suppresses energy intake and reduces body weight [10].” (Bathina et al., page 1164, Introduction).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the endothelin agonist of Leonard et al., Lipa et al., Gulati et al., Goligorksy et al., Detmar et al., and Nour et al. in conjunction with the BDNF disclosed by Bathina et al.
A person of ordinary skill in the art would be motivated to use BDNF of Barthina to increase the overall potency of the method of Leonard et al., Lipa et al., Gulati et al., Goligorksy et al., Detmar et al., and Nour et al because BDNF increases neurogenesis, which the same goal of the endothelin analog treatment.
A person of ordinary skill in the art would have a reasonable expectation of success because BDNF has been shown to increase neurogenesis and reduced apoptosis in clinical settings as disclosed by Bathina: “BDNF receptor activity not only enhanced neurogenesis but also suppressed apoptosis along with modulation in synaptic activity by a variety of signaling cascades. The participation of BDNF in the pathogenesis of cardiovascular diseases and diabetes mellitus by its critical role in inflammation, glucose and lipid metabolism is rather interesting. BDNF deficiency is associated with increased weight in mice and humans, and BDNF administration can reduce food intake and increase energy expenditure. Thus, BDNF seems to have an important role in several neurological diseases and type 2 diabetes mellitus.” (Bathina et al., page 1173, col. 2, para. 2).
Consequently, claim 10 is obvious over Leonard et al. in view of Lipa et al., Gulati et al., Goligorksy et al., Detmar et al. and Nour et al. and further in view of Bathina et al. and rejected.
Conclusion
No claim is allowed.
Claims 2, 7, 10, and 11 are objected to.
Claims 1-2 and 6-11 are rejected.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654