ETAILED 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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 16, 2026 has been entered.
Claim Objections
Claim 50 is objected to because of the following informalities: please amend “SEQ ID NO. 1” and “SEQ ID NO. 2” in lines 16 and 18 to “SEQ ID NO: 1” and “SEQ ID NO: 2”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 50, 51, 156, 157, and 158 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.
Claim 50 step (c) recites administering “an anti-ASC antibody specifically binding to a PYRIN-PAAD-DAPIN domain (PYD) or C-terminal caspase-recruitment domain (CARD) domain of the ASC inflammasome protein having an amino acid sequence at least 85% identical to rat ASC protein PYD or CARD domain having an amino acid sequence of SEQ ID NO. 1 or at least 85% identical to human ASC protein PYD or CARD domain having an amino acid sequence of SEQ ID NO. 2” [emphasis added].
It is unclear whether the emphasized “having” modifies the PYD or CARD domains or the ASC inflammasome protein. It is unclear whether SEQ ID NOs: 1 or 2 are intended to limit the anti-ASC antibody to an epitope comprising SEQ ID NOs: 1 or 2. Or whether the sequences are merely intended to limit the ASC protein to which the anti-ASC antibody binds, while not restricting the epitope to which the antibody binds. Additionally, SEQ ID NOs: 1 and 2 are present in the CARD domains of rat and human ASC, respectively. It is unclear how the PYD domain could have SEQ ID NOs: 1 or 2.
For the purpose of compact prosecution, the claims are interpreted as requiring anti-ASC antibody which binds to the PYD or CARD domain of ASC, wherein the ASC protein comprises SEQ ID NO: 1 or 2 – not where the anti-ASC antibody epitope is restricted to SEQ ID NOs: 1 or 2.
Claims 51, 156, 157, and 158 are rejected for depending from claim 50 and failing to remedy the indefiniteness.
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.
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.
Claim 50 is rejected under 35 U.S.C. 103 as being unpatentable over Keane et al. (US 2017/0003303 A1; Published: Jan 5, 2017) in view of Andres et al. (US 2014/0004543 A1; Published: Jan 2, 2014), Dick et al. (Nature Communications &: 11929; Published: Jun 22, 2016), Shichita et al. (Frontiers in Cellular Neuroscience. 8: 319; Published: Oct 14, 2014), and Schmidt et al. (Journal of Experimental Medicine. 213(5): 771-790; Published: April 11, 2016) and as evidenced by UniProt Q8CHK8 (Sequence Published: March 1, 2003) and UniProt Q9ULZ3 (Sequence Published: March 1, 2001).
Regarding the method of instant claim 50, Keane et al. claims 33-35 teach a method of treating a patient with CNS injury comprising administering a neuroprotective treatment to a patient with elevated levels of at least one inflammasome protein. Paragraphs 0009-0011 teach that comprises measuring at least one inflammasome protein, including ASC, in a biological sample obtained from a patient and comparing that protein level with a control or reference range in patients presenting with clinical symptoms of CNS injury. The profile of inflammasome proteins is indicative of the presence or severity of CNS injury and would be used to assess prognosis of patients receiving neuroprotective treatment. Paragraph 0026 and claim 46 teach that the abundance of one or more inflammasome proteins is indicative of the severity of CNS injury wherein CNS injury is defined to include stroke-related injury. Paragraph 0029 teaches that the protein signature may, in certain embodiments, comprise an elevated level for each of caspase-1 (e.g. p20 subunit of caspase-1), NLRP1, and ASC and patients who exhibit the protein signature may be selected or identified as having a CNS injury or a more severe CNS injury. Keane et al. claim 47 teaches that the biological sample tested may be serum. Regarding treating stroke comprising administering an anti-ASC antibody, Keane et al. teaches that neuroprotective treatments administered for the treatment of stroke include neutralizing anti-ASC antibodies; see paragraph 0034. Regarding the antibody administered in claim 50, Keane et al. teaches that neuroprotective antibodies bind to SEQ ID NOs: 1 or 2, which are both present in the CARD domains of rat or human ASC, respectively; see evidenced by UniProt Q8CHK8 and UniProt Q9ULZ3. SEQ ID NO: 1 is 100% identical to residues 178-193 of UniProt Q8CHK8 and SEQ ID NO: 2 is 100% identical to residues 182-195 of UniProt Q9ULZ3. Further, Keane et al. teaches that “a reduction in the level, abundance, or concentration of one or more inflammasome proteins (e.g. NLRP1, ASC, and caspase-1) is indicative of the efficacy of the neuroprotective treatment in the patient”; see paragraph 0035.
Keane et al. does not teach treating stroke patients with standard of care therapies nor that the strokes treated be of a particular subtype (ie. ischemic stroke, transient ischemic stroke, or hemorrhagic stroke). Additionally, despite stating that inflammasome proteins should be compared to a reference value or range, Keane et al. does not disclose a specific value or range. Finally, while Keane et al. teaches treating with an anti-ASC antibody, the reference does not teach that an anti-ASC antibody reduces ASC level in a patient.
Regarding the serum values of instant claim 50, Andres et al. teaches a similar method of using ASC as a marker for COPD. Figure 7 and Table 6 teaches that the serum concentration of ASC in healthy subjects averaged 272.513 pg/mL.
Like Keane et al., Andres et al. does not teach an anti-ASC antibody reduces the level of ASC in the patient.
Dick et al. teaches that ASC consists of a PYD and a CARD domain and is critical for activation of canonical inflammasomes, specifically NLRP3 and NLRC4 inflammasomes, and the subsequent activation of caspase-1 which leads to the maturation of proinflammatory cytokines; see Abstract.
Neither Keane et al., Andres et al. nor Dick et al. teach an antibody which reduces ASC level in a patient.
Shichita et al. teaches that ASC has been reported to be released into the extracellular space after cell death and activates inflammasomes in surrounding immune cells; see page 3, right column, third paragraph. While this doesn’t teach a composition which reduces ASC level, this does provide motivation for targeting ASC.
Furthermore, Shichita et al. teaches that damage-associated molecule patterns (DAMPs), including extracellular self DNA and RNA, hydrolyzed phospholipids, purines, and extracellular ASC, promote inflammasome activation in ischemic stroke and that DAMP-triggered, post-ischemic inflammation rarely lasts for a long period of time with the most intense inflammatory phase taking place within 7 days after stroke onset, and that the period of cerebral post-ischemic inflammation always ends, and thus, the mechanisms of its resolution must exist in ischemic brain; see Figure 1, Inflammatory DAMPs and Inflammation Suppression and Resolution sections. This teaching by Shichita et al. suggests that the natural phenomenon of elevated inflammasome proteins following stroke is transient and followed by the natural resolution of inflammasome-mediated inflammation and that any supportive care or standard care of stroke patients could result in the natural resolution of inflammation and reduction of inflammasome proteins, including ASC.
Given that Keane et al. provides a method for treating patients with suspected CNS injury, which includes stroke-related injury, by first measuring the level of inflammasome proteins in a biological sample and comparing said level(s) to a reference range to determine the presence of CNS injury, wherein an elevated level of inflammasome proteins would be suggestive of stroke and that Andres et al. teaches the average serum concentration of the inflammasome protein ASC in healthy subjects, it would have been obvious to one of ordinary skill in the art to modify the inflammasome protein assay for the same purpose of diagnosing CNS injury, or stroke, to comprise further comparing the level of ASC to the serum level of ASC in healthy subjects to diagnose stroke in a patient suspected of having a stroke.
Regarding the specific concentrations of ASC claimed, it would have obvious to optimize the threshold level of ASC for diagnosing stroke in view of the average ASC level in healthy subjects taught by Andres et al. Stroke requires prompt diagnosis and treatment to preserve life and prevent permanent brain damage and standard care requires physical evaluation and time-consuming medical imaging to diagnose. Given that inflammasome proteins, including ASC, were known to be elevated in stroke patients and that ASC serum concentration in healthy subjects is known, it would have been obvious to establish a threshold of serum ASC concentration through routine optimization wherein a level above suggest threshold would be indicative of stroke. An antibody-based assay conducted using a small amount of biological sample could provide a more rapid diagnosis compared to medical imaging allowing for swift critical care. Because a threshold serum ASC level has been established for diagnosing COPD and it was known in the art that stroke is associated with an elevated level of ASC, one would have had a reasonable expectation of success to establish such a threshold for stroke through routine optimization. Moreover, regarding the specific concentration of ASC, the instant claim requires identifying a single patient and administering to that patient and, given that Andres et al. teaches that the average serum ASC of healthy patients is 272.513 pg/mL and Keane et al. and Shichita et al. teach that stroke is associated with an elevated level of ASC in the patient, it would have been obvious to one of ordinary skill in the art to treat a patient having stroke symptoms and significantly elevated ASC, or greater than 300 pg/mL serum ASC, with a neuroprotective treatment as taught by Andres et al. and Keane et al. Further, it would have been obvious to one of ordinary skill and one would have had a reasonable expectation of success to use the neuroprotective anti-ASC antibody which binds to the CARD domain, specifically to SEQ ID NOs: 1 or 2, as taught by Keane et al. to treat a patient having stroke symptoms and elevated ASC level.
Finally, given that Dick et al. teaches that ASC is the critical component required for inflammasome oligomerization and that Shichita et al. teaches that extracellular ASC released following cell death and stimulate inflammasome activation in neighboring immune cells thereby propagating inflammasome activation and driving further inflammation, it would have been obvious to one of ordinary skill in the art to administer a composition which neutralizes ASC by binding to the CARD domain as taught by Keane et al. One would have a reasonable expectation of success that reducing ASC level would reduce further inflammasome activation and inflammation. Moreover, one of ordinary skill in the art would have a reasonable expectation of success interfering with caspase 1 activation and reducing IL-1beta and IL-18 inflammation because Schmidt et al. teaches that anti-ASC antibodies interfere with inflammasome activation and caspase 1 activation.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 51 is rejected under 35 U.S.C. 103 as being unpatentable over Keane et al. (US 2017/0003303 A1; Published: Jan 5, 2017) in view of Andres et al. (US 2014/0004543 A1; Published: Jan 2, 2014), Dick et al. (Nature Communications &: 11929; Published: Jun 22, 2016), Shichita et al. (Frontiers in Cellular Neuroscience. 8: 319; Published: Oct 14, 2014), and Schmidt et al. (Journal of Experimental Medicine. 213(5): 771-790; Published: April 11, 2016) as applied to claim 50 above, and further in view of Barrington et al. (Brain Pathology. 27: 205-212; Published: Feb 20, 2017).
The teachings of Keane et al. in view of Andres et al., Dick et al., Shichita et al., and Schmidt et al. as related to claim 50 above, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach that inflammasome proteins or ASC are elevated in ischemic stroke, transient ischemic stroke, or hemorrhagic stroke, specifically.
Barrington et al. teaches that during the acute phase of stroke, pro-inflammatory cytokines propagate the neuroinflammatory response through activation and recruitment of inflammatory cells via damage associated molecular pattern (DAMP) signaling which activates inflammasomes. Regarding inflammasome involvement in ischemic stroke, transient ischemic stroke, or hemorrhagic stroke as in instant claim 51, Barrington et al. teaches that NLRP3 inflammasome components and IL-1β and IL-18 were found to be elevated in models of ischemic stroke (permanent embolic MCAo (eMCAo)), transient ischemic stroke (transient middle cerebral artery occlusion (tMCAo)), and hemorrhagic stroke (intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH)).
Given that ischemic strokes and hemorrhagic strokes are the first and second most common subtype of stroke, it would have been obvious to apply the method of treating stroke patients taught by Keane et al. in view of Andres et al., Dick et al., and Shichita et al. in patients with clinical symptoms associated with ischemic stroke, transient ischemic stroke, or hemorrhagic stroke. Moreover, the finding that inflammasome proteins were elevated in mouse models of ischemic stroke, transient ischemic stroke, and hemorrhagic stroke would have provided a reasonable expectation of success.
Thus, the invention was prima facie obvious to one of ordinary skill in the art before the effective filing date of the application, as evidenced by the references.
Claims 156 and 157 are rejected under 35 U.S.C. 103 as being unpatentable over Keane et al. (US 2017/0003303 A1; Published: Jan 5, 2017) in view of Andres et al. (US 2014/0004543 A1; Published: Jan 2, 2014), Dick et al. (Nature Communications &: 11929; Published: Jun 22, 2016), Shichita et al. (Frontiers in Cellular Neuroscience. 8: 319; Published: Oct 14, 2014), Schmidt et al. (Journal of Experimental Medicine. 213(5): 771-790; Published: April 11, 2016), and Barrington et al. (Brain Pathology. 27: 205-212; Published: Feb 20, 2017) as applied to claims 50 and 51 above, and further in view of Bansal et al. (American Journal of Cardiovascular Drugs. 13(1): 57-69; Published: Feb 1, 2013).
The teachings of Keane et al. in view of Andres et al., Dick et al., Shichita et al., Schmidt et al., and Barrington et al. as related to claims 50 and 51 above, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach standard of care treatment for ischemic stroke.
Regarding the standard of care therapies in claims 156 and 157, Bansal et al. teaches the use of tissue plasminogen activators (tPA), antiplatelet medicine, and anticoagulants for acute ischemic stroke as on pages 3-8.
Given that Keane et al. in view of Andres et al., Dick et al., Shichita et al., and Barrington et al. teach a method for treating patients which comprises administering a standard of care therapy for stroke, it would have been obvious to initiate treatment of the patient diagnosed with stroke with standard of care therapies for the condition with which he/she has just been diagnosed. It would have been obvious to apply any of the standard of care therapies taught by Bansal et al. for the same purpose of treating a patient with ischemic stroke with a reasonable expectation of success.
Thus, the invention was prima facie obvious to one of ordinary skill in the art before the effective filing date of the application, as evidenced by the references.
Claim 158 is rejected under 35 U.S.C. 103 as being unpatentable over Keane et al. (US 2017/0003303 A1; Published: Jan 5, 2017) in view of Andres et al. (US 2014/0004543 A1; Published: Jan 2, 2014), Dick et al. (Nature Communications &: 11929; Published: Jun 22, 2016), Shichita et al. (Frontiers in Cellular Neuroscience. 8: 319; Published: Oct 14, 2014), Schmidt et al. (Journal of Experimental Medicine. 213(5): 771-790; Published: April 11, 2016), Barrington et al. (Brain Pathology. 27: 205-212; Published: Feb 20, 2017), and Bansal et al. (American Journal of Cardiovascular Drugs. 13(1): 57-69; Published: Feb 1, 2013) as applied to claims 156 and 157 above, and further in view of Connolly et al. (Stroke. 43(6): 1711-1737; Published: May 3, 2012).
The teachings of Keane et al. in view of Andres et al., Dick et al., Shichita et al., Schmidt et al., Barrington et al., and Bansal et al. as related to claims 156 and 157 above, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach standard of care treatment for hemorrhagic stroke.
Regarding the standard of care therapies in claim 158, Connolly et al. teaches treating subarachnoid hemorrhage, a type of hemorrhagic stroke, with coil embolization and aneurysm clipping as on pages 1720-1721.
Given that Keane et al. in view of Andres et al., Dick et al., Shichita et al., and Barrington et al. teach a method for treating patients which comprises administering a standard of care therapy for stroke, it would have been obvious to initiate treatment of the patient diagnosed with stroke with standard of care therapies for the condition with which he/she has just been diagnosed. It would have been obvious to apply any of the standard of care therapies taught by Connolly et al. for the same purpose of treating a patient with hemorrhagic stroke with a reasonable expectation of success.
Thus, the invention was prima facie obvious to one of ordinary skill in the art before the effective filing date of the application, as evidenced by the references.
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.
Claim 50 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-39, 46-49, and 56-59 of copending Application No. 19/562,607 in view of Keane et al. (US 2017/0003303 A1; Published: Jan 5, 2017), Andres et al. (US 2014/0004543 A1; Published: Jan 2, 2014), Dick et al. (Nature Communications &: 11929; Published: Jun 22, 2016), Shichita et al. (Frontiers in Cellular Neuroscience. 8: 319; Published: Oct 14, 2014), and Schmidt et al. (Journal of Experimental Medicine. 213(5): 771-790; Published: April 11, 2016) and as evidenced by by UniProt Q8CHK8 (Sequence Published: March 1, 2003) and UniProt Q9ULZ3 (Sequence Published: March 1, 2001).
Copending claims 5 and 7 teach a method of treating inflammasome-related inflammation comprising administering an anti-ASC antibody which binds to an epitope of ASC.
The copending claims do not teach treating stroke with an antibody that reduces ASC levels or interfere with caspase 1 activation, nor the serum level of ASC to identify a patient for treatment.
Keane et al. claims 33-35 teach a method of treating a patient with CNS injury comprising administering a neuroprotective treatment to a patient with elevated levels of at least one inflammasome protein. Paragraphs 0009-0011 teach that comprises measuring at least one inflammasome protein, including ASC, in a biological sample obtained from a patient and comparing that protein level with a control or reference range in patients presenting with clinical symptoms of CNS injury. The profile of inflammasome proteins is indicative of the presence or severity of CNS injury and would be used to assess prognosis of patients receiving neuroprotective treatment. Paragraph 0026 and claim 46 teach that the abundance of one or more inflammasome proteins is indicative of the severity of CNS injury wherein CNS injury is defined to include stroke-related injury. Paragraph 0029 teaches that the protein signature may, in certain embodiments, comprise an elevated level for each of caspase-1 (e.g. p20 subunit of caspase-1), NLRP1, and ASC and patients who exhibit the protein signature may be selected or identified as having a CNS injury or a more severe CNS injury. Keane et al. claim 47 teaches that the biological sample tested may be serum. Regarding treating stroke comprising administering an anti-ASC antibody, Keane et al. teaches that neuroprotective treatments administered for the treatment of stroke include neutralizing anti-ASC antibodies; see paragraph 0034. Regarding the antibody administered in claim 50, Keane et al. teaches that neuroprotective antibodies bind to SEQ ID NOs: 1 or 2, which are both present in the CARD domains of rat or human ASC, respectively; see evidenced by UniProt Q8CHK8 and UniProt Q9ULZ3. SEQ ID NO: 1 is 100% identical to residues 178-193 of UniProt Q8CHK8 and SEQ ID NO: 2 is 100% identical to residues 182-195 of UniProt Q9ULZ3. Further, Keane et al. teaches that “a reduction in the level, abundance, or concentration of one or more inflammasome proteins (e.g. NLRP1, ASC, and caspase-1) is indicative of the efficacy of the neuroprotective treatment in the patient”; see paragraph 0035.
Keane et al. does not teach treating stroke patients with standard of care therapies nor that the strokes treated be of a particular subtype (ie. ischemic stroke, transient ischemic stroke, or hemorrhagic stroke). Additionally, despite stating that inflammasome proteins should be compared to a reference value or range, Keane et al. does not disclose a specific value or range. Finally, while Keane et al. teaches treating with an anti-ASC antibody, the reference does not teach that an anti-ASC antibody reduces ASC level in a patient.
Regarding the serum values of instant claim 50, Andres et al. teaches a similar method of using ASC as a marker for COPD. Figure 7 and Table 6 teaches that the serum concentration of ASC in healthy subjects averaged 272.513 pg/mL.
Like Keane et al., Andres et al. does not teach an anti-ASC antibody reduces the level of ASC in the patient.
Dick et al. teaches that ASC consists of a PYD and a CARD domain and is critical for activation of canonical inflammasomes, specifically NLRP3 and NLRC4 inflammasomes, and the subsequent activation of caspase-1 which leads to the maturation of proinflammatory cytokines; see Abstract.
Neither Keane et al., Andres et al. nor Dick et al. teach an antibody which reduces ASC level in a patient.
Shichita et al. teaches that ASC has been reported to be released into the extracellular space after cell death and activates inflammasomes in surrounding immune cells; see page 3, right column, third paragraph. While this doesn’t teach a composition which reduces ASC level, this does provide motivation for targeting ASC.
Furthermore, Shichita et al. teaches that damage-associated molecule patterns (DAMPs), including extracellular self DNA and RNA, hydrolyzed phospholipids, purines, and extracellular ASC, promote inflammasome activation in ischemic stroke and that DAMP-triggered, post-ischemic inflammation rarely lasts for a long period of time with the most intense inflammatory phase taking place within 7 days after stroke onset, and that the period of cerebral post-ischemic inflammation always ends, and thus, the mechanisms of its resolution must exist in ischemic brain; see Figure 1, Inflammatory DAMPs and Inflammation Suppression and Resolution sections. This teaching by Shichita et al. suggests that the natural phenomenon of elevated inflammasome proteins following stroke is transient and followed by the natural resolution of inflammasome-mediated inflammation and that any supportive care or standard care of stroke patients could result in the natural resolution of inflammation and reduction of inflammasome proteins, including ASC.
Given that Keane et al. provides a method for treating patients with suspected CNS injury, which includes stroke-related injury, by first measuring the level of inflammasome proteins in a biological sample and comparing said level(s) to a reference range to determine the presence of CNS injury, wherein an elevated level of inflammasome proteins would be suggestive of stroke and that Andres et al. teaches the average serum concentration of the inflammasome protein ASC in healthy subjects, it would have been obvious to one of ordinary skill in the art to modify the inflammasome protein assay for the same purpose of diagnosing CNS injury, or stroke, to comprise further comparing the level of ASC to the serum level of ASC in healthy subjects to diagnose stroke.
Regarding the specific concentrations of ASC claimed, it would have obvious to optimize the threshold level of ASC for diagnosing stroke in view of the average ASC level in healthy subjects taught by Andres et al. Stroke requires prompt diagnosis and treatment to preserve life and prevent permanent brain damage and standard care requires physical evaluation and time-consuming medical imaging to diagnose. Given that inflammasome proteins, including ASC, were known to be elevated in stroke patients and that ASC serum concentration in healthy subjects is known, it would have been obvious to establish a threshold of serum ASC concentration through routine optimization wherein a level above suggest threshold would be indicative of stroke. An antibody-based assay conducted using a small amount of biological sample could provide a more rapid diagnosis compared to medical imaging allowing for swift critical care. Because a threshold serum ASC level has been established for diagnosing COPD and it was known in the art that stroke is associated with an elevated level of ASC, one would have had a reasonable expectation of success to establish such a threshold for stroke through routine optimization. Moreover, regarding the specific concentration of ASC, the instant claim requires identifying a single patient and administering to that patient and, given that Andres et al. teaches that the average serum ASC of healthy patients is 272.513 pg/mL and Keane et al. and Shichita et al. teach that stroke is associated with an elevated level of ASC in the patient, it would have been obvious to one of ordinary skill in the art to treat a patient having stroke symptoms and significantly elevated ASC, or greater than 300 pg/mL serum ASC, with a neuroprotective treatment as taught by Andres et al. and Keane et al. Further, it would have been obvious to one of ordinary skill and one would have had a reasonable expectation of success to use the neuroprotective anti-ASC antibody which binds to the CARD domain, specifically to SEQ ID NOs: 1 or 2, as taught by Keane et al. to treat a patient having stroke symptoms and elevated ASC level.
Finally, given that Dick et al. teaches that ASC is the critical component required for inflammasome oligomerization and that Shichita et al. teaches that extracellular ASC released following cell death and stimulate inflammasome activation in neighboring immune cells thereby propagating inflammasome activation and driving further inflammation, it would have been obvious to one of ordinary skill in the art to administer a composition which neutralizes ASC by binding to the CARD domain as taught by Keane et al. One would have a reasonable expectation of success that reducing ASC level would reduce further inflammasome activation and inflammation. Moreover, one of ordinary skill in the art would have a reasonable expectation of success interfering with caspase 1 activation and reducing IL-1beta and IL-18 inflammation because Schmidt et al. teaches that anti-ASC antibodies interfere with inflammasome activation and caspase 1 activation.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Claim 51 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-39, 46-49, and 56-59 of copending Application No. 19/562,607 in view of Keane et al. (US 2017/0003303 A1; Published: Jan 5, 2017), Andres et al. (US 2014/0004543 A1; Published: Jan 2, 2014), Dick et al. (Nature Communications &: 11929; Published: Jun 22, 2016), Shichita et al. (Frontiers in Cellular Neuroscience. 8: 319; Published: Oct 14, 2014), and Schmidt et al. (Journal of Experimental Medicine. 213(5): 771-790; Published: April 11, 2016) as applied to claim 50 above, and further in view of Barrington et al. (Brain Pathology. 27: 205-212; Published: Feb 20, 2017).
The teachings of the claims of copending Application No. 17/255,653, Keane et al., Andres et al., Dick et al., Shichita et al., and Schmidt et al. as related to claim 50 above, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach that inflammasome proteins or ASC are elevated in ischemic stroke, transient ischemic stroke, or hemorrhagic stroke, specifically.
Barrington et al. teaches that during the acute phase of stroke, pro-inflammatory cytokines propagate the neuroinflammatory response through activation and recruitment of inflammatory cells via damage associated molecular pattern (DAMP) signaling which activates inflammasomes. Regarding inflammasome involvement in ischemic stroke, transient ischemic stroke, or hemorrhagic stroke as in instant claim 51, Barrington et al. teaches that NLRP3 inflammasome components and IL-1β and IL-18 were found to be elevated in models of ischemic stroke (permanent embolic MCAo (eMCAo)), transient ischemic stroke (transient middle cerebral artery occlusion (tMCAo)), and hemorrhagic stroke (intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH)).
Given that ischemic strokes and hemorrhagic strokes are the first and second most common subtype of stroke, it would have been obvious to apply the method of treating stroke patients taught by the copending claims in view of Keane et al., Andres et al., Dick et al., and Shichita et al. in patients with clinical symptoms associated with ischemic stroke, transient ischemic stroke, or hemorrhagic stroke. Moreover, the finding that inflammasome proteins were elevated in mouse models of ischemic stroke, transient ischemic stroke, and hemorrhagic stroke would have provided a reasonable expectation of success.
Thus, the invention was prima facie obvious to one of ordinary skill in the art before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Claims 156 and 157 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-39, 46-49, and 56-59 of copending Application No. 19/562,607 in view of Keane et al. (US 2017/0003303 A1; Published: Jan 5, 2017), Andres et al. (US 2014/0004543 A1; Published: Jan 2, 2014), Dick et al. (Nature Communications &: 11929; Published: Jun 22, 2016), Shichita et al. (Frontiers in Cellular Neuroscience. 8: 319; Published: Oct 14, 2014), Schmidt et al. (Journal of Experimental Medicine. 213(5): 771-790; Published: April 11, 2016), and Barrington et al. (Brain Pathology. 27: 205-212; Published: Feb 20, 2017) as applied to claims 50 and 51 above, and further in view of Bansal et al. (American Journal of Cardiovascular Drugs. 13(1): 57-69; Published: Feb 1, 2013).
The teachings of the copending claims in view of Keane et al., Andres et al., Dick et al., Shichita et al., Schmidt et al., and Barrington et al. as related to claims 50 and 51 above, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach standard of care treatment for ischemic stroke.
Regarding the standard of care therapies in claims 156 and 157, Bansal et al. teaches the use of tissue plasminogen activators (tPA), antiplatelet medicine, and anticoagulants for acute ischemic stroke as on pages 3-8.
Given that the copending claims in view of Keane et al., Andres et al., Dick et al., Shichita et al., and Barrington et al. teach a method for treating patients which further comprises administering a standard of care therapy for stroke, it would have been obvious to initiate treatment of the patient diagnosed with stroke with standard of care therapies for the condition with which he/she has just been diagnosed. It would have been obvious to apply any of the standard of care therapies taught by Bansal et al. for the same purpose of treating a patient with ischemic stroke with a reasonable expectation of success.
Thus, the invention was prima facie obvious to one of ordinary skill in the art before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Claim 158 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-39, 46-49, and 56-59 of copending Application No. 19/562,607 in view of Keane et al. (US 2017/0003303 A1; Published: Jan 5, 2017), Andres et al. (US 2014/0004543 A1; Published: Jan 2, 2014), Dick et al. (Nature Communications &: 11929; Published: Jun 22, 2016), Shichita et al. (Frontiers in Cellular Neuroscience. 8: 319; Published: Oct 14, 2014), Schmidt et al. (Journal of Experimental Medicine. 213(5): 771-790; Published: April 11, 2016), Barrington et al. (Brain Pathology. 27: 205-212; Published: Feb 20, 2017)and Bansal et al. (American Journal of Cardiovascular Drugs. 13(1): 57-69; Published: Feb 1, 2013) as applied to claims 156 and 157 above, and further in view of Connolly et al. (Stroke. 43(6): 1711-1737; Published: May 3, 2012).
The teachings of the copending claims in view of Keane et al., Andres et al., Dick et al., Shichita et al., Schmidt et al., Barrington et al., and Bansal et al. as related to claims 156 and 157 above, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach standard of care treatment for hemorrhagic stroke.
Regarding the standard of care therapies in claim 158, Connolly et al. teaches treating subarachnoid hemorrhage, a type of hemorrhagic stroke, with coil embolization and aneurysm clipping as on pages 1720-1721.
Given that the copending claims in view of Keane et al., Andres et al., Dick et al., Shichita et al., and Barrington et al. teach a method for treating patients which further comprises administering a standard of care therapy for stroke, it would have been obvious to initiate treatment of the patient diagnosed with stroke with standard of care therapies for the condition with which he/she has just been diagnosed. It would have been obvious to apply any of the standard of care therapies taught by Connolly et al. for the same purpose of treating a patient with hemorrhagic stroke with a reasonable expectation of success.
Thus, the invention was prima facie obvious to one of ordinary skill in the art before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s amendments filed November 17, 2025 are acknowledged. Any rejection not repeated above is resolved by amendment.
Terminal disclaimers to obviate the nonstatutory double patenting rejections over the claims of U.S. Patent No. 8,685,400 B2 and copending Application No. 17/255,653 were filed November 17, 2025. The nonstatutory double patenting rejections over the claims of U.S. Patent No. 8,685,400 B2 and copending Application No. 17/255,653 are withdrawn.
Regarding the rejection under 35 U.S.C. 112a, Applicant argues that the number of antibodies which bind the epitopes claimed by sequence are finite and would be readily understood and recognized by a person of ordinary skill in the art.
First, the claim recites “an anti-ASC antibody specifically binding to a PYRIN-PAAD-DAPIN domain (PYD) or C-terminal caspase-recruitment domain (CARD) domain of the ASC inflammasome protein having an amino acid sequence at least 85% identical to rat ASC protein PYD or CARD domain having an amino acid sequence of SEQ ID NO. 1 or at least 85% identical to human ASC protein PYD or CARD domain having an amino acid sequence of SEQ ID NO. 2”. Thus, the claim requires an antibody that binds to the only two domain present in ASC, the PYD and CARD domains. And while ASC must have at least 85% identity to SEQ ID NOs: 1 or 2, the claim does not require that the antibody binds to these sequences, the claim merely limits the species homology of ASC to which the antibody binds.
Moreover, even if the claim did limit the antibody to binding to a particular epitope, this hypothetical limitation may decrease the number of antibodies within the scope of the claims, but would not appreciably change the scope of the genus when measured in the hundreds of antibodies. Further limiting of the epitope would not provide a structure for the antibodies being claimed as stated in the 112a rejection as an epitope does not provide a shared structure for the antibody. A structure function correlation must inform the structure of the antibodies used in the claimed method. Limiting the antibodies to those that bind an epitope sequence would fail to provide a structure function correlation and the art does not provide it either.
However, the claim now requires an anti-ASC antibody and paragraph 0074 of the instant disclosure teaches that there are many ASC antibodies. The “interfering with activation of caspase-1 in the inflammasome cascade pathway and reducing ASC level and inflammation in the patient” naturally flows from the administration of the anti-ASC antibody.
Regarding the rejection under 35 U.S.C. 103, Applicant argues that claim 50 is nonobvious because it comprises a step of identifying a patient for treatment having an expression level of serum ASC greater than 300 pg/ml or a serum-derived extracellular vesicle level of ASC greater than 70 pg/ml. Further, Applicant argues that Andres et al., which is relied upon for the normal level of serum ASC from which one of ordinary skill would optimize the level of ASC above which to treat, does not teach the serum ASC level associated with stroke nor serum-derived EV ASC level. Examples 4 and 5 of Andres et al. use the same study population which include controls or “obviously healthy individuals”. Table 6 provides the average ASC value in healthy controls is 272.513 pg/ml. Indeed, Andres et al. is evaluating ASC levels as a biomarker for COPD – not stroke. However, “obviously healthy individuals” as described in paragraph 0234, are not individuals presenting with stroke and would perform the same function as in Andres et al. – providing a reference level for normal ASC levels from which one could optimize the level above which treatment should be administered. As described in the rejection above, it would have been obvious to treat a patient presenting with stroke symptoms and elevated ASC levels with an anti-ASC antibody because Keane et al. teaches that stroke is associated with elevated ASC level and treating stroke with an anti-ASC antibody.
Conclusion
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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