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 .
Status of Claims
Claims 1, 3-14, 17, 19, 23, and 25-33 are pending in the instant application.
Claims 2, 15-16, 18, 20-22, and 24 have been canceled.
Withdrawn Objections/Rejections
Applicant’s amendment is sufficient to overcome the objection to the abstract. This objection is hereby withdrawn.
Applicant’s amendment to the specification is sufficient to overcome the objection due to the presence of a symbol Applicant noted was erroneous at Page 20, Last Paragraph, of the remarks filed October 8th, 2025. This objection is hereby withdrawn.
Applicant’s amendment is sufficient to overcome the objection to claims 4, 6-16, and 24-28 for being in improper form. Claims 15-16 and 24 have been canceled, rendering the objection thereof moot. This objection is hereby withdrawn.
Applicant’s amendment is sufficient to overcome the rejection of Claims 1-3, 5, 17, and 19-23 under 35 U.S.C. 112(a). Claims 2 and 20-22 have been canceled, rendering the rejection thereof moot. This rejection is hereby withdrawn.
Applicant’s amendment is sufficient to overcome the rejection of Claims 1-3 and 5 under 35 U.S.C. 102(a)(1). Claim 2 has been canceled, rendering the rejection thereof moot. This rejection is hereby withdrawn.
Applicant’s amendment is sufficient to overcome the rejection of Claims 17-19 under 35 U.S.C. 102(a)(1). Claim 18 has been canceled, rendering the rejection thereof moot. This rejection is hereby withdrawn.
Applicant’s amendment is sufficient to overcome the rejection of Claims 20-23 under 35 U.S.C. 102(a)(1). Claims 20-22 have been canceled, rendering the rejection thereof moot. This rejection is hereby withdrawn.
Applicant has canceled Claims 18 and 20-22, rendering the rejection thereof on the ground of nonstatutory double patenting moot. This rejection is hereby withdrawn.
Drawings
Acknowledgement is made of the replacement drawings received October 8th, 2025. These drawings are acceptable to overcome the objection raised in the non-final rejection mailed April 8th, 2025. This objection is hereby withdrawn.
Claim Rejections - 35 USC § 112
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.
Claims 1, 3-14, 17, 23, 25-32 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 a method for the treatment of a viral infection caused by an influenza virus, does not reasonably provide enablement for a method for prevention of any viral infection caused by an RNA virus. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to a method of treating and/or preventing a viral infection comprising administering thapsigargin and/or a derivative of thapsigargin defined as a compound of Formula (I) or Formula (Ia) as recited at instant Claim 1.
Breadth of the invention:
The scope of the claimed invention is broad, as it is drawn to the treatment and/or prevention of any viral infection caused by an RNA virus. This includes an array of infections caused by RNA viruses, both known presently, or viral infections caused by RNA viruses that have yet to be discovered. Can the Applicant simply “reach through” and obtain patent protection against viral infections caused by viruses that are unknown at the time of filing?
State of the prior art and predictability in the art:
The invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F. 2d 833, 839, 166, USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F. 2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F. 2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F. 2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Level of ordinary skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing chemical compounds for particular activities. The synthesis of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can be employed, developing a therapeutic method, as claimed, prior to synthesizing and testing compounds is generally not well-known or routine, given the complexity of certain biological systems.
The amount of direction provided and working examples:
Beginning at Page 60 of the instant specification, Applicant has disclosed several examples demonstrating the efficacy of the instantly claimed invention in treating viral infections.
Example 1 sufficiently discloses the materials and methods necessary for undertaking the examples that follow.
At Page 63, Example 2 demonstrates that by raising extracellular Ca2+ levels, production of influenza virus was reduced.
Beginning at Page 63, Example 3 demonstrates that treating NPTr cells with thapsigargin resulted in an inhibition of influenza virus.
Beginning at Page 65, Example 4 demonstrates antiviral activity of thapsigargin in NPTR cells, NHBE cells, and porcine myoblasts against influenza virus.
Beginning at Page 66, Example 5 demonstrates an elevation of type I interferon signaling in response to influenza virus infection when cells have been treated with thapsigargin.
Beginning at Page 67, Example 6 provides evidence that thapsigargin’s antiviral activity is due, at least in part, to post-transcriptional interference of influenza virus.
Beginning at Page 67, Example 7 provides evidence of thapsigargin’s antiviral activity is due, at least in part, to causing endoplasmic reticulum stress.
Beginning at Page 68, Example 8 provides comparative data indicating that ER stress alone is not sufficient for antiviral activity.
Beginning at Page 69, Example 9 demonstrates thapsigargin facilitates store-operated Ca2+ entry (SOCE), and this is mechanistically important to inhibition of virus production.
Beginning at Page 71, Examples 10-11 provides further evidence that facilitation of the SOCE function is important in thapsigargin’s antiviral activity.
Common to each of these examples is the demonstration that thapsigargin demonstrates antiviral activity against influenza virus. These examples are not sufficient, then, to be enabling for the treatment of any viral infection caused by an RNA virus, nor are they sufficient to enable the prevention of viral infections, including those caused by influenza.
Within the specification, “specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group.” See MPEP 608.01(p).
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here that Applicant is not enabled for treating viral infections caused by RNA viruses other than influenza, as a person having ordinary skill in the art would need to engage in undue experimentation to determine which viral infections are suitable for treatment with thapsigargin, with no assurance of success.
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.
Claim 14 is 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 14 recites the limitation “wherein the thapsigargin or pharmaceutically acceptable salt, stereoisomer, or derivative thereof is obtainable by hydrolysis of thapsigargin.” This limitation renders the claim indefinite, as the broadest reasonable interpretation would suggest thapsigargin obtained by hydrolysis of thapsigargin. It is unclear how hydrolysis of thapsigargin would generate thapsigargin itself. Further, with respect to the derivatives thereof, it is indefinite as to when, where, and how the hydrolysis of thapsigargin occurs.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 12-13, 17, and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Johansen et. al. (WO 2008/033466 A2; hereinafter referred to as Johansen).
Beginning at Page 206, Johansen teaches a hepatitis C virus (HCV) replicon assay used to screen compounds for activity against HCV (taught to be an RNA virus at Page 20, Lines 22-23) viral RNA replication. Results from this assay, including IC50 values are presented at Table 1 beginning on Page 2. At Page 4, thapsigargin is reported to have an IC50 value of 0.0113 mM against HCV.
At Page 215, Claim 1, Johansen teaches a pharmaceutical composition comprising a first agent selected from the agents of Table 1, which would include thapsigargin and a second agent selected from agents of Tables 4 and 5, and, further, at Page 216, Claim 10, teaches the composition is formulated for oral administration.
At Page 25, in table 4, Zanamivir, Oseltamivir, Peramivir, Amantadine, and Rimantadine are listed as antiviral agents suitable for use in the claimed invention, in addition to thapsigargin.
This reads on the limitations of Claim 1. While Johansen teaches the inclusion of a second agent, the transitional phrase comprising recited at Claim 1 allows for the inclusion of other agents. Per MPEP 2111.03, I., “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)”.
Claims 19 and 33 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CAS Registry File 1924667-24-2 (entered into STN June 3rd, 2016; obtained from the internet October 28th, 2025; hereinafter referred to as CAS Registry File).
CAS Registry File teaches the following compound:
PNG
media_image1.png
250
349
media_image1.png
Greyscale
This compound reads on a compound of formula (I) and/or formula (II) as recited at instant Claim 19 when the variables are defined as follows:
R1 is OH.
R2 is OH.
R3 is OH.
R4 is OH.
A is attached to B and the moiety -A-B- is -O-.
Regarding Claim 33, this compound is Compound O.
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.
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, 3-4, 6-11, 25-26, 28, and 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over Caplan (US2002/0132770 A1; hereinafter referred to as Caplan) in view of Fujioka et. al. (“”A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection”, Nature Communications, 4, 2013; cited on Information Disclosure Statement filed March 7th, 2024; hereinafter referred to as Fujioka).
At Pages 3-4, Paragraph 0047, Caplan teaches the invention is useful for treatment of viral diseases, including rhinosinusitis, a viral infection that is caused by an RNA virus. At Page 24, Claim 1, Caplan claims a method of treating rhinosinusistis or alleviating the symptoms of rhinosinusitis comprising administering an agent that permits the release of proteins from the endoplasmic reticulum. Thapsigargin is such an agent, evidenced by Caplan at Page 8, Paragraph 0144.
At Page 4, Paragraph 0052, Caplan teaches the method use agents that cause the release of Ca2+ from the endoplasmic reticulum.
At Page 4, Paragraph 0056, Caplan teaches thapsigargin is an agent useful in the methods presented by the invention.
At Page 16, Paragraph 0232, Caplan teaches the therapeutics compositions can be used in solid or liquid forms.
Caplan does not teach that thatpsigargin is useful in treating viral infections caused by an RNA virus as instantly claimed, but rather teaches the treatment of viral infections generically. Further, Caplan does teach thapsigargin is useful in the treatment of rhinosinusitin, an RNA virus, and this would suggest to a person having ordinary skill in the art that administration of thapsigargin could be useful in the treatment of other viral infections caused by an RNA virus.
At Page 2, Last Paragraph, Fujioka states, “We next evaluated the effect of thapsigargin, an inhibitor of sarcoendoplasmic reticulum Ca2+ ATPases, on IAV infection. The entire progeny of 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 rasies [Ca2+]i by blocking the sarcoendoplasmic reticulum Ca2+ ATPases pumps, which thereby causes endoplasmic reticulum stores to become depleted, this result might indicate that intracellular Ca2+ released from endoplasmic reticulum is crucial for IAV infection and replication.”
Taken together, Caplan teaches thapsigargin is useful for treatment of viral infections via a mechanism of releasing Ca2+ from endoplasmic reticulum, and Fujioka suggests that such a release of Ca2+ from the endoplasmic reticulum can hinder infection and replication of influenza A (IAV), thereby treating a viral infection caused by an influenza virus as recited at Claims 3-4.
Applying KSR exemplary rationale D, it would have been prima facie obvious for a person having ordinary skill in the art to practice the instantly claimed method of treating a viral infection caused by an influenza virus comprising administering thapsigargin, as thapsigargin was known to release Ca2+ from the endoplasmic reticulum, motivated by the teaching of Fujioka that such a release of Ca2+ hinders IAV replication and/or infection.
Regarding the amounts and frequency of administration of thapsisgargin, as Caplan taught administration of thapsigargin for the treatment of rhinosinusitis, the instantly claimed ranges and/or frequencies of administration would have been arrived at by a person having ordinary skill in the art via routine optimization. Per MPEP 2144.05, II., A., “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
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.
The provisional rejection of Claims 1, 3, 5, 17, and 23 on the ground of nonstatutory double patenting as being unpatentable over claim 35 of copending Application No. 17/045,083 (reference application) is maintained and extended to Claims 4, 6-15, and 25-32.
Applicant has not properly addressed the specific grounds of rejection as discussed in the previous office action. Therefore, the rejection will be maintained until a terminal disclaimer is filed or the claims are amended to obviate the rejections.
Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 35 of the reference application is drawn to a method of treating or preventing a viral infection caused by an RNA virus comprising administering compounds of formula (II), which includes the instantly claimed thapsigargin.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1, 3-14, 17, 19, 23, and 25-33 are rejected.
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANIEL JOHN BURKETT whose telephone number is (703)756-5390. The examiner can normally be reached Monday - Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/D.J.B./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624