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 .
DETAILED ACTION
Claims 1-5 and 13-25 are under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/16/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because “Figure” should be written as “Fig. or FIG.” Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: Correct the spelling of “coroviridae” to “coronaviridae” and “faction” to “fraction” (p. 10).
Appropriate correction is required.
Claim Objections
Claims 1-5, 13-15, 18-25 are objected to because of the following informalities:
Claim 1: “influenza virus interfering particles (DIPs)” should be “influenza virus defective interfering particles (DIPs)”.
Claim 2: “defecting interfering particles” should be “defective interfering particles”.
Claim 3, 4, 5, 13, 14, 18, 19, 20, 21, 22, 23: Similar to claim 2, add a comma after claim #. For example, in claim 3, type “claim 1, wherein” or in claim 18, type “claim 15, wherein”.
Claim 13: Remove the comma after wherein and “influenza virus interfering particles (DIPs)” should be “influenza virus defective interfering particles (DIPs)”.
Claims 15, 25: “influenza virus interfering particles (DIPs)” should be “influenza virus defective interfering particles (DIPs)”.
Claim 18: “influenza interfering virus particles (DIPS)” should be “influenza virus defective interfering particles (DIPs)”. Insert (IAV) after “influenza A virus” in claim 18 so that “IAV” in claim 19 is clear. Also, capitalize “influenza A”, e.g., Influenza A.
Claim 21: Change “administration of the DIP” to “administration of the DIPs”.
Claim 24: Capitalize “influenza A”, e.g., Influenza A.
Appropriate correction is required.
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 1-5, 13-25 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 using Influenza virus A defective interfering particles as a therapeutic treatment in vitro (e.g., cell culture experiments with Calu-3 cells [human lung epithelial cells]) against one example of virus from the family Coronaviridae SARS-CoV-2, does not reasonably provide enablement for the use of influenza virus defective interfering particles (DIPs), other than Influenza A, against all of the positive-strand RNA viruses within this family or for prophylactic use of the composition. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claims 1-5, 13-25 as submitted 08/16/2023.
In making a determination as to whether an application has met the requirements for enablement under 35 U.S.C. 112 P1, the courts have put forth a series of factors. See, In re Wands, 8 USPQ2d 1400, at 1404 (CAFC 1988). The factors considered include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. Id. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered. In the present case, the factors deemed relevant are those of: the breadth of the claims, the state of the art, the absence of working examples, and the quantity of experimentation necessary.
Nature of the invention and breadth of the claims:
Claims 1-5, 13-25 of the present invention are drawn to a method for prophylactic or therapeutic treatment of coronaviridae infection in an individual comprising administering the individual influenza virus defective interfering particles (DIPs). An example of an influenza virus defective interfering particles is Influenza A virus defective interfering particles (IAV DIP). An example of coronaviridae is SARS-CoV-2. Individuals include human, cat, ferret, dog, and mink. Mucosal and intranasal administration are both considered. Time of administration and effective amounts are also very generally considered.
The relative skill of those in the art:
The level of skill in the art is high and would include, e.g., Ph.D. level scientists, medical doctors (MDs), and veterinarians (VMD/DVM).
State of the art and the unpredictability of the art:
In her article, Repurposing therapeutics for potential treatment of SARS-CoV-2: a review(Viruses, 2020;12(7): 1-19; published 30 June 2020; see PTO-892 Notice of References Cited), Santos summarized drugs and therapies with either theoretical, in vitro, or in vivo antiviral activity against SARS-CoV or MERS-CoV to strategically identify therapeutic options that can be used or repurposed for the treatment of SARS-CoV-2 (p. 1, Introduction). “Mechanistic and in vitro analyses suggest multiple promising therapeutic options with potential for repurposing to treat patients with COVID-19. Therapeutics with particularly high potential efficacy for repurposing include camostat mesylate, remdesivir, favipiravir, tocilizumab, baricitinib, convalescent plasma, and humanized monoclonal antibodies” (p.1, Abstract). In Table 1, Santos organized the therapeutic options into three classes – Immunomodulators, Antibiotics and Other Medications. For both SARS-CoV and MERS, very few in vivo studies exist for therapeutics. However, the ones with some in vivo evidence include the Immunomodulators class, particularly interferons and steroidals such as methylprednisolone and dexamethasone. Santos states that “Remdesivir reduced overall virus replication and lung damage in rhesus macaques infected with MERS-CoV…It also showed therapeutic efficacy against SARS-CoV in a mouse model” (p. 3). Additionally, Santos noted some successful patient outcomes were achieved with combination therapy with lopinavir/ritonavir (LPV/r) in both SARS-CoV and MERS-CoV (p. 4). Overall, though, more research, in vivo experimentation, and clinical trials are warranted.
In her article, Vaccines against COVID-19 (Anaesth Crit Care Pain Med. 2020;39(6):703-705; published 20 October 2020; see PTO-892 Notice of References Cited), Lochte reports:
(1) The duration of immunity to COVID-19 induced by infection or vaccination is not known, and some reports suggest that antibody-mediated immunity may last for only a few months (p. 703).
(2) Several hundred COVID-19-specific vaccines are at various stages of development in academia and industry and make use of a variety of different generic platforms, such as inactivated virus, purified recombinant viral proteins with or without adjuvant, replicating and non-replicating viral vectored antigens, antigen-encoding DNA or mRNA. Some of them build on technologies approved for other vaccines, others are novel and have not yet been used for large-scale vaccination (p.703).
(3) In addition to these studies, more than 200 trials have been registered so far on ClinicalTrials.gov, but safety, efficacy or immunogenicity data are lacking for most of them (p. 704).
According to a GAO-21-207 COVID-19 Vaccine and Therapeutic Efforts report published in November 2020 (See PTO-892 Notice of References Cited):
(1) As of October 15, 2020, Operation Warp Speed had publicly announced financial support for the development and manufacturing of six vaccine candidates for COVID-19. In selecting vaccine candidates, Operation Warp Speed officials said that they focused on candidates that had initial data on clinical safety and efficacy and the ability to enter late stage clinical trials by fall 2020, and the ability to rapidly scale up manufacturing (p.13).
(2) Four candidates’ clinical trial protocols provide limited details on how the vaccine developers will analyze their safety and efficacy data, specifically for population subgroups (e.g., the elderly, people with comorbidities, or racial/ethnic groups) or sample sizes needed for such subgroup analyses. Unless vaccine developers collect sufficient data for a subgroup analysis, it may not be possible to identify the potential for different safety or efficacy results for one or more subgroups, even if vaccine candidates are found safe and effective in the aggregate for the general population. The protocols reference separate analysis plan documents that may contain more information on their methodologies and planned analyses (p.17).
(3) Scaled up production of COVID-19 vaccines and therapeutics through Operation Warp Speed consisted of the following challenges: limited manufacturing capacity; disruptions to manufacturing supply chains; difficult technology transfer processes; and gaps in available workforce.
(4) For therapeutics, FDA has issued four EUAs as of November 9, 2020. However, the evidence to support FDA’s COVID-19 therapeutic EUA decisions has not always been transparent, because the agency has not uniformly disclosed information from its scientific review of the safety and effectiveness data at the time of each authorization (p. 20). The EUAs for therapeutics include:
one for a new use for two existing drugs—chloroquine and hydroxychloroquine—on March 28, 2020;
one for a new drug—remdesivir—on May 1, 2020;
one for a new biologic—COVID-19 convalescent plasma—on August 23, 2020;
one for another new biologic—bamlanivimab, a monoclonal antibody—on November 9, 2020.
After reviewing additional scientific evidence, about 2.5 months after its authorization (on June 15, 2020), FDA revoked the EUA for chloroquine and hydroxychloroquine (due to adverse event reporting). As of November 9, 2020, three therapeutics—remdesivir, COVID-19 convalescent plasma, and bamlanivimab—remain authorized for emergency use for COVID-19, of the four FDA has authorized to date.
Even with swift vaccine development and EUAs for some therapeutics, concerns remain about unintended consequences according to FDA officials and stakeholder groups such as potential decrease in clinical trial participation; vaccine hesitancy; and drug shortages (p. 31). All of these consequences could have a negative impact on obtaining adequate data to support efficacy and use of the vaccine or therapeutic.
To summarize, the state of the art does provide some evidence, albeit fraught with difficulty, of predictability for therapeutic therapies for SARS-CoV-2 success as encompassed by instant claims. However, it does not provide evidence of predictability for the use of influenza virus defective interfering particles (DIPs), other than Influenza A, as a prophylactic or therapeutic against all of the positive-strand RNA viruses within the Coronaviridae family.
The amount of direction and the working examples provided:
For claims 1-5, 13-25, the term “Coronaviridae” is used broadly. Burrell et al (2017)(See PTO-892 Notice of References Cited) note that the family Coronaviridae “[e]ncompasses a broad spectrum of animal and human viruses. It consists of two sub-families, Coronavirinae [Orthocoronavirinae] and Torovirinae. Members of the subfamily Coronavirinae [Orthocoronavirinae] are subdivided into four genera – Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus with only some of the viruses within these genera shown to cause disease in humans” (p. 437). Similarly “influenza virus” is also broad (as recited in claims 1 and 15).
The disclosure only contains data, albeit, in vitro not in vivo data, showing that SARS-CoV-2 (from Betacoronavirus) replication is abrogated by Influenza A virus defective interfering particles (IAV DIP) treatment in vitro and that IAV DIPs may play a role in induction of the innate immune response. The disclosure does not provide a sufficient number of virus examples or in vitro or in vivo experiments with a diverse number of virus examples from the family Coronaviridae to support the claims as broadly written.
Animal and human clinical trials are not featured in the specification nor are efficacy and safety data nor are sufficient descriptions of experimental oversight such as through Institutional Animal Care and Use Committees (IACUC), Institutional Review Boards (IRBs) or data and safety monitoring boards (DSMBs).
Thus, the instant disclosure offers no reasonable guidance or direction to use the claimed method of therapeutically or prophylactically treating a viral infection with Coronaviridae, beyond therapeutically treating SARS-CoV-2, in an individual.
Quantity of experimentation necessary:
As discussed above undue experimentation would be required to practice the claimed invention commensurate with the scope of the claims. Reasonable correlation must exist between the scope of the claims and scope of enablement set forth. In view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in specification, and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
In view of the foregoing, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The 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 1-5 and 13-25 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.
Claims 1-5 and 13-25 as submitted 08/16/2023.
Claim 1 and Claim 13.: The use of “individual” influenza virus is unclear and not found in the specification. It is unclear if the intention here is “comprising administering to the individual the influenza virus interfering particles (DIPs).
Claim 13. ii.: The use of “faction” and its meaning is unclear in this claim and in the specification. It is unclear if “faction” has a special meaning on its own or if it is simply a typo of “fraction”.
Claim 19: The term “effective amount” in relation to a dose for therapeutically or prophylactically treating a viral infection is not sufficiently supported by the specification (See MPEP 2173.05(c) III. “Effective Amount”. While some in vitro studies are provided, in vivo trials and results are not included in the disclosure.
Claim 21: For the phrase “administration of the DIP is effected within one to two weeks before potential exposure “, the term “effected” is unclear. For improved language, it is recommended to change to “administration of the DIP is given within one to two weeks”.
Claim 23: The phrase “therapeutic effective amounts of DIPs DI244 or DIP OP7 are not sufficiently supported by the specification. (See MPEP 2173.05(c) III. “Effective Amount”. While some in vitro studies are provided, in vivo trials and results are not included in the disclosure.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
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.
Claims 1-5, 13-20, 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Dimmock et al. (Dimmock) (US8435508B2) in view of Dimmock et al. (2015) (Dimmock 2015), and in view of Lei et al. (Lei)(2020)(See PTO-892 Notice of References Cited).
Claims 1-5, 13-20, 22-25 as submitted on 08/16/2023.
Dimmock teaches “A pharmaceutical composition comprising a cloned defective interfering (DI) influenza A virus, comprising a nucleotide sequence of an RNA segment 1 of the cloned DI influenza A virus consisting of (a) a sequence selected from SEQ ID NO: 1 (Reference claim 1) which has a 100% match with that of the instant application’s claim 1 (see Result 3, US-12-302-194A-1, us-18-546-690-1.align150.rni)(as recited in claims 1, 2, 15, 18, 24, 25). Dimmock also teaches the invention includes a method of preventing or treating influenza A in a subject comprising administering an effective amount of a cloned DI influenza A virus particle (p. 16, col. 15, lines 29-32) (as recited in claims 5 and 18) as well as teaches that the preferred compositions or medicaments are for mucosal delivery (as recited in claim 16). The subject can include humans, animals or birds (p. 17, col. 17, line 12)(as recited in claim 14). Of the various mucosal delivery options available, the intranasal route is the most practical as it offers easy access with relatively simple devices that have already been mass produced (p. 15, col. 14, lines 62-66) (as recited in claim 17). Dimmock further states (1) that an individual known or suspected of being infected with an influenza A virus can be treated for the infection, even if symptoms of infection have yet to be observed or infection diagnosed. The individual can be administered with the cloned DI influenza A medicament as soon as possible when an infection is suspected (as partially recited in claim 20). Individuals can also be infected as soon as possible after having been in contact with other individuals of the same or different species and who are known or suspected to be infected with influenza A (p. 14, col 12, lines 25-29)(as partially recited in claim 20) and (2) that the dosage regime may consist of a single dose of medicament. For claim 20, routine experimentation procedures would have allowed one to arrive at an ideal time to administer the DIPs to an individual post-infection to achieve optimal results and identify a time within the range already included in the specification, e.g., within 24 hours (p. 15) (See MPEP 2144.05 II. A. Routine Optimization, Optimization Within Prior Art Conditions or Through Routine Experimentation).
Dimmock did not teach DIPs DI244 or DIP OP7.
Dimmock 2015, however, teaches the application of DI virus to protect from virus-associated diseases in vivo using as an example a highly active cloned influenza A DI genome and virus, e.g., DI 244, that protects broadly in preclinical trials against different subtypes of influenza A and against non-influenza A respiratory viruses, such as genetically distinct influenza B virus and the paramyxovirus pneumonia virus of mice. This influenza A-derived DI genome protects by two totally different mechanisms: molecular interference with influenza A replication and by stimulating innate immunity that acts against non-influenza A viruses (Abstract, p. 3768 and p. 3770). As indicated in the title, Dimmock 2015 suggests possible pan-specific treatment of respiratory viral diseases. Dimmock 2015 further teaches “Influenza DI RNA 244 is interesting as it contains no major regions of double-strandedness but after intranasal administration with DI virus stimulates production of type I interferon in the lung (as recited in claim 13 iii.). This is highly significant as it suggests that 244 DI virus could protect against all interferon-sensitive non-influenza A respiratory viruses, including those grouped together as ILI” (influenza-like illnesses)(p. 10)(as recited in claim 23).
Both Dimmock and Dimmock 2015 do not teach SARS-CoV-2.
Lei teaches SARS-CoV- 2 which belongs to the Coronaviridae family, Orthocoronavirinae
subfamily, Betacoronaviruses genus, Sarbecovirus subgenus (p. 2)(as recited in claims 3, 4, and 5). Lei also teaches that [a]fter SARS-CoV, SARS-CoV-2 is the second virus that originated
from bats and could infect human beings of Sarbecovirus (SARS-CoV as recited in claim 22). Although not well understood, preliminary research by Lei suggests that SARS-CoV-2, a variant of SARS-CoV, induces substantial but delayed IFN-β production (p. 2); SARS-CoV-2 proteins interfere with IFN-β activation (p. 2); SARS-CoV-2 is sensitive to IFN-β treatment in a Calu-3 cell infection model (e.g., it decreased the amount of viral transcripts and the production of replicative viruses in a dose-dependent manner)(p. 6); and that IFN therapy could be an option for COVID-19 treatment (p.6).
One of ordinary skill in the art would have been motivated to combine the teachings of Dimmock 2015 (e.g., Influenza A DI RNA 244 with potential to stimulate an interferon response) and Lei (e.g., the demonstration of SARS-CoV-2 sensitivity to IFN-β treatment), and Dimmock (e.g., for eligible “individual” as a human) to arrive at the current invention. The teachings collectively suggest that Influenza A virus (IAV) defective interfering particles (DIPs) could be used against interferon-sensitive non-influenza A respiratory viruses such as SARS-CoV-2 (COVID-19) in individuals because IAV DIPs appear to induce an innate immune response, and more specifically, an interferon response (see MPEP 2143, Rationale G. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention).
One of ordinary skill in the art would have had a reasonable expectation of success for using IAV DIPs, particularly DI244 as a therapeutic treatment of SARS-CoV-2 (COVID-19) infection in an individual. From 2013 and onward, Dimmock teaches the idea that defective interfering IAVs can be administered to a human subject as a therapeutic post-infection from Influenza A virus as well as discloses different types of compositions for defective interfering (DI) Influenza A virus such as DI244. Concurrent immunopathological work on influenza viruses, defective IAVs as well as other respiratory viruses but especially the emergent and pandemic causing SARS-CoV-2, reveals specific ways that interferon responses are targeted during infection by the pathogen in question and ways to augment the interferon response by administration of IAV DIPs. As a result, there is at least some degree of predictability that an IAV DIPs composition and a method of therapeutically treating a respiratory viral infection, could work. As a note, obviousness does not require absolute predictability, but at least some degree of predictability is required (See MPEP 2143.02 II At Least Some Degree of Predictability is Required). Similarly, as noted above for the discussion of SARS-CoV-2 therapeutics (§ 112(a)), the global pandemic nature of SARS-CoV-2 and the resulting, in some case severe, clinical outcomes observed post-infection necessitated rapid exploration of different therapeutics even though many options were not successful in trials or did not receive or maintain emergency use authorization (See MPEP 2143.02 III Predictability is Determined at the Relevant Time).
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Cornelius whose telephone number is (571) 272-0860. The examiner can normally be reached M-F, 0930-1700.
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/C.C./Examiner, Art Unit 1672
/M FRANCO G SALVOZA/Primary Examiner, Art Unit 1672