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 .
Claim Status
Claims 35, 43-59 and 61 are pending. Claim 59 is withdrawn. Claims 35, 43-58 and 61 are rejected.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/24/2025 has been entered.
Response to Amendment/Arguments
The declaration under 37 CFR 1.132 filed 10/24/2025 is insufficient to overcome the rejection of claims 35, 43-54 and 56-59 based upon obviousness under 35 USC 103 as set forth in the last Office action. The declaration provides experimental results for the therapeutic effect of thapsigargin in various formulations. The information provided seems to expose the natural course of optimizing a dosage wherein not every dose in a range will have the same effects and a person of ordinary skill would counterbalance the desired therapeutic effect with side effects for treatment. For example, in Experiment 1 mild adverse effects were reported at doses of 15 and 20 mg/kg with the oral lipid-based solution containing thapsigargin whereas in Experiment 2 no adverse effects were detected at 15 and 20 mg/kg with the oral lipid-free formulation (pages 2 and 3 of the declaration). Therefore, the declarant clearly demonstrates that even dosages above 10mg/kg, which is the upper limit of the claimed range, can be safely used in further studies. In the remarks, Applicant is arguing unexpected results of a particular dosage that falls within the range of the prior art. Even if administration of particularly low dosages were unexpectedly effective, these results would not be commensurate in scope with the instant claims which claim a broader range. MPEP 716.02(d) states:
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)
The fact that the higher limit of 2000mg per dose taught by Bolotina et al. could be expected to result in adverse effects does not mean that other doses within the prior art range are not obvious. Rather, if a person of ordinary skill sought to administer the lowest dose necessary to achieve the therapeutic effect they would be motivated to begin optimizing at the lower end of the disclosed range. Caplan et al. and Fujioka et al. in combination teach that thapsigargin has a utility for treating viral diseases such as influenza A which is caused by an RNA virus. The dosage taught by Bolotina is not directed to treating a viral disease however the instant claims embrace preventing a viral infection and page 36 of the instant specification states, “[t]he subject is typically one that has been exposed to the virus.” The instant claims do not require that that the subject has contracted the virus; therefore, methods wherein thapsigargin is administered for any purpose would be embraced by the claim.
For these reasons claims 35, 43-58 and 61 are rejected as set forth below.
Election/Restrictions
Applicant’s elected species is not allowable therefore search and examination has been limited to claims embracing the elected species which are claims 35, 43-58 and 61. Claims 35, 43-58 and 61 have been examined to the extent that they are readable on the elected embodiment.
Claims 59-60 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 35, 43, 45-49, 52-54, 56-58 and 61 are rejected under 35 U.S.C. 103 as being unpatentable over US 20020132770 A1 by Caplan et al. in view of Fujioka et al. A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection. Nat Commun 4, 2763 (2013)., and US 9599605 B1 by Bolotina.
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
The prior art teaches methods of treating viral diseases by administering agents that cause release of Ca2+ from the endoplasmic reticulum or stimulate IP3 receptor activity and recite thapsigargin as a suitable agent in accordance with instant claims 35 and 45-48 (paragraphs [0047], [0052], [0053] and [0056]).
Regarding instant claims 56 and 58, Caplan et al. note that the prior art method embraces pulmonary administration wherein thapsigargin is administered in the form of an aerosol (paragraph [0058]). Regarding instant claim 61, Caplan et al. teach liquid preparations for oral administration (paragraph [0243]).
Regarding instant claim 49, the prior art discloses pharmaceutical compositions comprising the prior art compound and a pharmaceutically acceptable carrier (paragraph [0232]).
Instant claim 5 requires that the subject is a mammal. Caplan et al. tested nebulized thapsigargin on mice (paragraph [0289]).
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art discloses the use of thapsigargin for treating viral diseases but does not specify that the viral infection is caused by an RNA virus. The instant claims embrace preventing a viral infection and page 36 of the instant specification states, “[t]he subject is typically one that has been exposed to the virus.” The instant claim does not require that that the subject has been in contact with the virus; therefore, methods wherein thapsigargin is administered for any purpose would be embraced by the claim. Additionally, Fujioka et al. do not teach the dosages of the instant claims.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Fujioka et al. evaluate the role of Ca2+ in influenza A virus internalization and infection. Fujioka et al. state (page 2):
We next evaluated the effect of thapsigargin, an inhibitor of sarcoendoplasmic reticulum Ca2+ ATPases, on IAV infection. The titre of progeny viruses was markedly increased for MDCK cells treated with thapsigargin at a low dose compared with that for control cells, and dose-dependently reduced at higher doses (Supplementary Fig. S3a). Given that thapsigargin raises [Ca2+]i by blocking the sarcoendoplasmic reticulum Ca2+ ATPases pumps, which thereby causes endoplasmic reticulum stores to become depleted21, this result might indicate that intracellular Ca2+ released from endoplasmic reticulum is crucial for IAV infection and replication.
Regarding instant claims 52-54, the prior art notes that the test cells were infected with A/Puerto Rico/8/34 (H1N1; PR8) virus strain (Supplementary Figure S3, page 3 of supplement).
Accordingly, a person of ordinary skill would have been motivated to use the method of treating viral disease by administering thapsigargin disclosed by Caplan et al. to treat subjects with an RNA virus such as influenza A because thapsigargin was shown to dose-dependently decrease the titre of progeny viruses as taught by Fujioka et al.
Regarding the 1 ng to 10 mg per kg body weight and 1 ng to 10 µg per kg body weight dose ranges required by claims 35 and 43, Bolotina discloses that a dosage of from about 0.001 mg to about 2000 mg of SOCE activator per kilogram of body weight per day can be used for treatment (Col. 17, lines 57-60) wherein doses around .001mg/kg overlap with instant claims 35 and 43. Accordingly, a person of ordinary skill would have been motivated to modify the combined method of Caplan et al. and Fujioka et al. to test varying dosages comprising thapsigargin within the ranges taught by Bolotina et al.
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over US 20020132770 A1 by Caplan et al. in view of Fujioka et al. A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection. Nat Commun 4, 2763 (2013). and US 9599605 B1 by Bolotina. as applied to claims 35, 43, 45-49, 52-54, 56-58 and 61 above, and further in view of Antigny et al. (Cell Calcium 49 (2011) 115–127).
Caplan et al., Fujioka et al., and Bolotina in combination teach a method of treating a viral infection caused by an RNA virus by administering thapsigargin but do not specify that the compound is an inhibitor of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) pump. Antigny et al. discuss how thapsigargin facilitates store-operated Ca2+ entry (SOCE) and state, “[e]xperimentally, SOCE is frequently stimulated by blocking the sarco-endoplasmic reticulum Ca2+-ATPases (SERCA), with drugs like thapsigargin (TG) that passively deplete the ER” (page 115, paragraph 1). Accordingly, thapsigarin is an inhibitor of the SERCA pump as taught by Antigny et al.
Claims 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over US 20020132770 A1 by Caplan et al. in view of Fujioka et al. A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection. Nat Commun 4, 2763 (2013)., and US 9599605 B1 by Bolotina. as applied to claims 35, 43, 45-49, 52-54, 56-58 and 61 above, and further in view of Razonable RR. Antiviral drugs for viruses other than human immunodeficiency virus. Mayo Clin Proc. 2011;86(10):1009-1026.
Caplan et al., Fujioka et al., and Bolotina in combination teach a method of treating a viral infection caused by an RNA virus by administering thapsigargin but do not specify combination therapies comprising additional antiviral agents.
Razonable provides a review of “antiviral drugs for viruses other than human immunodeficiency virus” (title) and lists amantadine, rimantadine, oseltamivir, etc. as antiviral drugs for influenza as required by instant claims 50-51 (pages 1015-1016). Regarding the motivation to combine thapsigargin with an additional antiviral agent, MPEP 2144.06 states:
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)
Accordingly, a person of ordinary skill seeking to improve treatment outcomes would have been motivated to modify the combined method of Caplan et al., Fujioka et al., and Bolotina to treat a viral infection caused by an RNA virus by administering thapsigargin in combination with one of the antiviral drugs disclosed by Razonable.
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.
Claims 35 and 43-58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of co-pending Application No. 17768003 in view of US 20020132770 A1 by Caplan et al., Fujioka et al. A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection. Nat Commun 4, 2763 (2013)., Antigny et al. (Cell Calcium 49 (2011) 115–127), Razonable RR. Antiviral drugs for viruses other than human immunodeficiency virus. Mayo Clin Proc. 2011;86(10):1009-1026., and US 9599605 B1 by Bolotina.
Co-pending claims 1 and 3 disclose a method of treating or preventing human influenza A viruses or a respiratory syncytial virus by administering thapsigargin which is the basis of subject matter rendered obvious relative to claims 35 and 43-54 and 56-58. The combined teachings of Caplan et al., Fujioka et al., Antigny et al., Bolotina, and Razonable relative to claims 35 and 43-54 and 56-58 are incorporated here by reference. The instant claims are deemed to be variants of the subject matter of the co-pending application for the same reasons as under 35 USC 103.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/A.A.C./Examiner, Art Unit 1626
/JOSEPH K MCKANE/Supervisory Patent Examiner, Art Unit 1626