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 .
Priority
This application is a national phase entry pursuant to 35 U.S.C. § 371 of International Application No. PCT/US2021/022089, filed March 12, 2021, which claims priority to U.S. Provisional Application No. 63/002,165, filed on March 30, 2020, and U.S. Provisional Application No. 63/122,858, filed on December 8, 2020.
Claims Status
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on April 06, 2026. Claims 2, 3, and 9 are canceled. Claims 1, 4-8, and 10-23 are pending and under examination.
Action Summary
The objection to claims 1 and 8 is withdrawn in light of the claim amendment.
Claims 1 and 8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn in light of Applicant’s explanation and the examples provided in paragraph [0049].
Claims 1, 4-8, 11-20, and 22 rejected under 35 U.S.C. 103 as being unpatentable over Jones et al (US2019/0076396 A1) in view of Tsuji et al (. 2012 Aug 17;5(8):837–852) and Malaviya et al (Pharmacol Ther. 2017 Jun 19; 180:90–98), are maintained.
Claim 10 rejected under 35 U.S.C. 103 as being unpatentable over Jones et al (US2019/0076396 A1) in view of Tsuji et al (. 2012 Aug 17;5(8):837–852) and Malaviya et al (Pharmacol Ther. 2017 Jun 19; 180:90–98) as applied to claims 1, 4-8, 11-20, and 22, in further view of Lee et al (Pain Physician. 2012 Jul-Aug;15(4):287-96), is maintained.
Claims 21 and 23 rejected under 35 U.S.C. 103 as being unpatentable over Jones et al (US2019/0076396 A1) in view of Tsuji et al (. 2012 Aug 17;5(8):837–852) and Malaviya et al (Pharmacol Ther. 2017 Jun 19; 180:90–98) as applied to claims 1, 4-8, 11-20, and 22, in further view of Wu et al (J Microbiol Immunol Infect. 2020 Mar 11;53(3):368–370) and Wang et al (Vascul Pharmacol. 2013 Jan;58(1-2):71-7. Epub 2012 Jul 28), are maintained.
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.
Claims 1, 4-8, 11-20, and 22 remain rejected under 35 U.S.C. 103 as being unpatentable over Jones et al (US2019/0076396 A1) in view of Tsuji et al (. 2012 Aug 17;5(8):837–852) and Malaviya et al (Pharmacol Ther. 2017 Jun 19; 180:90–98).
Jones teaches a non-alcoholic formulation of resiniferatoxin (RTX) for intrathecal, intraarticular, intraganglionic or periganglionic administration comprising from about 10 μg/mL to about 200 μg/mL RTX in a formulation having enough monosaccharide to keep the specific gravity between 1.0 and 1.3 and can be solubilized in a mixture, of PEG (0-40%), polysorbate (0-5%) and cyclodextrin (0-5%) in an aqueous buffer solution with saline and a pH from about 6.5 to about 7.5 and containing an antioxidant. (See paragraph [0007].) Intraganglionic administration” is administration to within a ganglion. Jones teaches intraganglionic administration can be achieved by direct injection into the ganglion and also includes selective nerve root injections, or periganglionic administration, in which the compound passes up the connective tissue sleeve around the nerve and enters the ganglion from the nerve root just outside the vertebral column. (See paragraph [0009].) Nerve root injection is a species of nerve block. Jones also teaches the aqueous buffer with saline can be considered a pharmaceutically acceptable carrier that includes water and saline. The formulation Preferably comprises from about 25-50 μg/mL RTX. (See paragraph [0008].) Moreover, Jones teaches RTX is a known transient receptor potential cation channel subfamily V member 1 (TrpV1) agonist. (See paragraph [0004].) Jones further teaches activation of TrpV1 typically occurs at the nerve endings via application of painful heat and is up-regulated during certain types of inflammatory stimuli. (See paragraph [0003].) Lastly, Jones teaches for intraganglionic administration, a typical volume injected is from 50 to 300 microliters delivering a total amount of RTX that ranges from about 50 nanograms (0.5 μg) to about 50 micrograms. Often the amount administered is from 200 ng (0.2 μg) to 10 μg. RTX can be administered as a bolus or infused over a period of time, typically from 1 to 10 minutes. 0.5 μg to 50 μg reads on claim 8.
Jones does not teach treating pulmonary inflammatory disease that includes inflammation associated with mechanical ventilation, acute respiratory distress syndrome (ARSD) and chronic obstructive pulmonary disease (COPD).
Tsuji teaches SA13353 (1-[2-(1-adamantyl) ethyl]-1-pentyl-3-[3-(4-pyridyl) propyl] urea), a novel TRPV1 agonist, inhibits tumor necrosis factor-alpha (TNF-α) production by the activation of capsaicin-sensitive afferent neurons and reduces the severity of symptoms in kidney injury, lung inflammation, arthritis, and encephalomyelitis has been demonstrated. These results suggest that TRPV1 agonists may act as anti-inflammatories in certain inflammatory and autoimmune conditions in vivo. (See Abstract.) Tsuji also teaches TRPV1 agonists capsaicin, resiniferatoxin, and SA13353 (1- [2-(1- adamantyl) ethyl]-1-pentyl-3-[3-(4-pyridyl) propyl] urea) attenuate renal tumor necrosis factor (TNF)-[Symbol font/0x61] mRNA expression, increase renal interleukin (IL)-10 mRNA expression, and improve the condition of ischemia/reperfusion-induced renal injury in rats. (See lines 19-22 of section 3 of page 840.) Moreover, Tsuji teaches the effects of orally administered TRPV1 agonists on leukocyte infiltration in LPS-induced acute lung injury and ovalbumin-induced allergic airway inflammation in rodents was investigated. In LPS-induced lung injury, capsaicin and SA13353 attenuated neutrophil infiltration and the increase in TNF-[Symbol font/0x61] and cytokine-induced neutrophil chemoattractant (CINC)-1 levels. In allergic airway inflammation, SA13353 tended to inhibit leukocyte infiltration and attenuated the increase in IL-4 and IL-12p40. These results suggest that at least somatosensory TRPV1 may play an anti-inflammatory role in lung inflammation. Inducing the cough reflex and modifying airway inflammation may be important functions of TRPV1 in body homeostasis. (See 24-32 of section 4 of page 841.) Tsuji further teaches SA13353 also reduces the levels of a number of cytokines, including TNF-[Symbol font/0x61], IL-1β, IL-12p40, IL-17, and interferon (IFN)-γ. (See lines 12-13 of page 842.)
Malaviya teaches increased levels of tumor necrosis factor (TNF-α) have been linked to a number of pulmonary inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), sarcoidosis, and interstitial pulmonary fibrosis (IPF). TNFα plays multiple roles in disease pathology by inducing an accumulation of inflammatory cells, stimulating the generation of inflammatory mediators, and causing oxidative and nitrosative stress, airway hyperresponsiveness and tissue remodeling. TNF-targeting biologics, therefore, present a potentially highly efficacious treatment option. (See Abstract.) Moreover, Malaviya teaches in animal models of ALI or ARDS induced by endotoxin, mechanical ventilation, or extracorporeal circulation, TNFα has been implicated in disease pathogenesis. (See the last paragraph of page 6.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use the formulation taught by Jones for treating COPD and ARDS, and
ARDS associated with mechanical ventilation, which is inflammation associated with mechanical ventilation by reducing TNF-α to give Applicant’s claimed method. One would have been motivated to do so, because not only Jones teach RTX which is a TrpV1 agonist and because Tsuji teaches RTX as a TrpV1 agonist can inhibit or reduce the increased levels of TNF-α and TRPV1 agonists on leukocyte infiltration in LPS-induced acute lung injury and ovalbumin-induced allergic airway inflammation, and also because increased levels of tumor necrosis factor (TNF-α) have been linked to a number of pulmonary inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). One would reasonably expect RTX to effectively treat COPD, ARDS, and ARDS associated with mechanical ventilation which is an inflammation disease associated with mechanical ventilation with success.
Claim 10 remains rejected under 35 U.S.C. 103 as being unpatentable over Jones et al (US2019/0076396 A1) in view of Tsuji et al (. 2012 Aug 17;5(8):837–852) and Malaviya et al (Pharmacol Ther. 2017 Jun 19; 180:90–98) as applied to claims 1, 4-8, 11-20, and 22, in further view of Lee et al (Pain Physician. 2012 Jul-Aug;15(4):287-96).
The teachings of Jones, Tsuji, and Malaviya have been discussed supra.
Jones, Tsuji, and Malaviya collectively do not teach epidural administration.
Lee teaches RTX is highly selective for sensory nerve terminals expressing TRPV1 receptors without affecting proprioception and motor function. In many animal studies, RTX has been found useful for inflammatory pain, postoperative incisional pain, and bone cancer pain. It has been administered by variable routes: systemic by subcutaneous, intrathecal, epidural, intraganglionic, perineural, and directly to peripheral nerve endings. (See second paragraph of the left column of page 288.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the obvious method taught by Jones, Tsuji, and Malaviya by including epidural administration in order to treat COPD, ARDS, and ARDS associated with mechanical ventilation which is an inflammation disease associated with mechanical ventilation by reducing the underline pain associated with them. One would have been motivated to do so, because Lee teaches RTX has been administered by variable routes: systemic by subcutaneous, intrathecal, epidural, intraganglionic, perineural, and directly to peripheral nerve endings for treating inflammatory pain, postoperative incisional pain, and bone cancer pain. (See second paragraph of the left column of page 288.) One would reasonably expect to successfully treat COPD, ARDS, and ARDS associated with mechanical ventilation which is an inflammation disease associated with mechanical ventilation by reducing the underline pain associated with them with the obvious method taught Jones, Tsuji, and Malaviya.
Note: the statement in the prior Office Action that “Jones, Tsuji, and Malaviya collectively do not teach epidural administration” was an inadvertent error. As clearly set forth in the body of the rejection below, epidural administration is addressed by Lee et al. in the rejection of claim 10. The correct statement for the rejection of claims 21 and 23 is that Jones, Tsuji, and Malaviya collectively do not specifically teach pulmonary arterial hypertension (PAH) or pulmonary inflammatory disease associated with COVID-19, as recited in claims 21 and 23m respectively. Wang et al. and Wu et al. are relied upon for teaching these additional disease limitations.
Claims 21 and 23 remain rejected under 35 U.S.C. 103 as being unpatentable over Jones et al (US2019/0076396 A1) in view of Tsuji et al (. 2012 Aug 17;5(8):837–852) and Malaviya et al (Pharmacol Ther. 2017 Jun 19; 180:90–98) as applied to claims 1, 4-8, 11-20, and 22, in further view of Wu et al (J Microbiol Immunol Infect. 2020 Mar 11;53(3):368–370) and Wang et al (Vascul Pharmacol. 2013 Jan;58(1-2):71-7. Epub 2012 Jul 28).
The teachings of Jones, Tsuji, and Malaviya have been discussed supra.
Jones, Tsuji, and Malaviya collectively do not specifically teach pulmonary arterial hypertension (PAH) or pulmonary inflammatory disease associated with COVID-19..
Wu teaches COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many COVID-19 patients develop acute respiratory distress syndrome (ARDS), which leads to pulmonary edema and lung failure, and have liver, heart, and kidney damages. These symptoms are associated with a cytokine storm, manifesting elevated serum levels of IL-1β, IL-2, IL-7, IL-8, IL-9, IL-10, IL-17, G-CSF, GM-CSF, IFNϒ, TNFα, IP10, MCP1, MIP1A and MIP1B. (See the second paragraph of the left column bridging the right column of page 368.)
Wang teaches monocrotaline-induced pulmonary arterial hypertension is attenuated by TNF-α antagonists via the suppression of TNF-α expression and NF-κB pathway in rats. (See Title.) Moreover, Wang teaches inflammation is involved in various types of human pulmonary arterial hypertension (PAH), especially in PAH-associated connective tissue diseases. Although the pathogenesis of pulmonary hypertension has still remained largely unclear, TNF-α has been reported as a key pro-inflammatory cytokine in severe pulmonary hypertension and emphysema. (See Abstract.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the obvious method taught by Jones, Tsuji, and Malaviya by including PAH and ARDS associated with covid-19 which is a disease of inflammation associated with covid-19. One would have been motivated to do so, because not only Wu teaches many COVID-19 patients develop acute respiratory distress syndrome (ARDS), which leads to pulmonary edema and lung failure, and have liver, heart, and kidney damages and are manifested by elevated serum levels of TNF-α among others and also because TNF-α antagonists can attenuate pulmonary arterial hypertension via the suppression of TNF-α expression. One would reasonably expect to successfully treat PAH and ARDS associated with covid-19 which is a disease of inflammation associated with covid-19 with the obvious method taught Jones, Tsuji, and Malaviya.
Acknowledgement is made of the receipt and entry of Applicant’s argument/remarks filed on April 06, 2026.
Applicant argues that Tsuji does not identify resiniferatoxin (RTX) as a suitable agent for treating pulmonary inflammatory disease and instead emphasizes SA13353 as a preferred TRPV1 agonist with advantageous properties. Applicant further argues that Tsuji directs one of ordinary skill in the art away from RTX.
Applicant’s argument is not persuasive. Tsuji expressly teaches that TRPV1 agonists, including RTX, capsaicin, and SA13353, attenuate inflammatory response and reduce cytokine expression associated with inflammation conditions, including lung inflammation. Tsuji specifically teaches that TRPV1 agonists attenuated neutrophil infiltration and inflammatory cytokine production in LPS-induced acute lung injury and allergic airway inflammation, and further teaches RTX is itself a TRPV1 agonist. The fact that Tsuji additionally studies or characterizes SA13353 as a novel agonist does not criticize, discredit, or other discourage the use of RTX. Merely describing one compound as advantageous or novel does not constitute teaching away from the expressly disclosed use of other members of the same class. See In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
Applicant additionally argues that Tsuji acknowledges uncertainty regarding the role of TRPB1 in inflammation and therefore one of ordinary skill in the art would lack motivation or reasonable expectation of success.
Applicant’s argument is not persuasive. A reference is not required to establish absolute predictability or certainty of success to support a conclusion of obviousness Rather, only a reasonably expectation of success is required. Tsuji nevertheless teaches anti-inflammatory effects associated with TRPV1 agonists in vivo, including attenuation of cytokines and leukocyte infiltration in lung inflammation models. Malyviya further teaches that TNF-α is implicated in pulmonary diseases including COPD, ALI, and ARDS. Collectively, the references provide sufficient evidence that modulation of inflammatory cytokines through TRPV1 agonists would reasonably have been expected to provide therapeutic benefit in pulmonary inflammation diseases.
Applicant further argues that neither Tsuji nor the other cited references teach or suggest the claimed route of administration for treating pulmonary inflammatory diseases, including epidural, peri-ganglionic, or intra-ganglionic administration.
Applicant’s argument is not persuasive. Jones expressly teaches RTX formulations suitable for intraganglionic and periganglionc administration. Jones further teaches direct ganglionic injection and selective nerve root injections. Therefore, Jones itself teaches the claimed nerve-targeted administration routed recited in claim 1. Additionally, Lee teaches RTX administration through epidural, intrathecal, intraganglionic, and perineural delivery routes. Thus, the cited references collectively teach the claimed route of administrations.
Applicant argues that the references fail to provide a link between nerve-targeted RTX administration and treatment of pulmonary inflammatory disease.
In response, Applicant’s argument is not persuasive. Jones teaches nerve-targeted administration of RTX, including intraganglionic and periganglionic administration. Tsuji teaches TRPV1 agonists, including RTX, attenuate inflammatory cytokines and lung inflammation. Malaviya teaches TNF-α is implicated in pulmonary inflammatory diseases including COPD and ARDS. Wu teaches COVID-19 associated ARDS involves elevated inflammatory cytokines including TNF-α, and Wang teaches TNF-α signaling is implicated in PAH pathology. Collectively, the references provide articulated reasoning with rational underpinning that reducing inflammatory cytokine signaling through TRPV1 agonist administration would have been reasonably expected to provide therapeutic benefit in pulmonary inflammatory diseases, including COVID-19-associated pulmonary inflammation and PAH.
Applicant’s argument that Wu and Wang merely identify inflammatory conditions without teaching RTX is also not persuasive. Wu and Wang are not relied upon for teachings RTX administration itself, which is taught by Jones and Tsuji. Rather, Wu and Wang are upon for teaching the additional disease limitations recited in claim 21 and 23, specifically pulmonary inflammatory disease associated with COVID-19 and PAH, respectively. A determination of obviousness may properly rely on multiple references for different claim limitations. See In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986).
Accordingly, the combinations of Jones, Tsuji, Malyviya, Wu, Wang, and Lee collectively teaches or suggests all limitations of the rejected claims and provides sufficient motivation to combine with a reasonable expectation of success.
Conclusion
Claims 1, 4-8, and 10-23 are not allowed.
THIS ACTION IS MADE FINAL. 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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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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