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 .
Election/Restrictions
Applicant's election with traverse of Composition Administered; and the species corresponding to Micafungin, in the reply filed on July 17, 2026 is acknowledged. The traversal is on the ground(s) that examination of all of the claims does not create an undue search burden on the examiner. This is not found persuasive because the inventions require a different field of search (e.g., employing different search strategies or search queries) since a search of a particular compound/formulation would not necessarily lead to art reading on different compounds/formulations. In the instant case, the species are structurally different, i.e., small peptides or small molecules; and these species are not obvious variants of each other.
Applicant further elected with traverse of another Composition Administered; and the species corresponding to recombinant RSV antibody which is Palivizumab, in the reply filed on July 17, 2026 is acknowledged. The traversal is on the ground(s) that examination of all of the claims does not create an undue search burden on the examiner. This is not found persuasive because the inventions require a different field of search (e.g., employing different search strategies or search queries) since a search of a particular compound/formulation would not necessarily lead to art reading on different compounds/formulations. In the instant case, the species are structurally different, i.e., small peptides, small molecules or antibodies; and these species are not obvious variants of each other.
Examiner’s Note: It is to be noted that the selection written in the alternative were stated as examples for the Applicant/Inventor to choose that were relevant to the instantly claimed invention. Claim 7 states ” The method of claim 1, wherein the compound is administered in combination with an anti-viral agent or vaccine”; implied the composition administered for method of treating or preventing a viral infection comprising administering an effective amount an RNA-dependent RNA Polymerase (RdRP) inhibitory compound included anti-viral agent. Therefore, the alternate examples with and/or option were stated.
Applicant’s election with traverse with regard to treatment; and the selection is of a human subject/patient which is RSV, in the reply filed on July 17, 2026 is acknowledged. The traversal is on the ground(s) that examination of all of the claims does not create an undue search burden on the examiner. This is not found persuasive because the inventions require a different field of search (e.g., employing different search strategies or search queries) since a search of a particular compound/formulation would not necessarily lead to art reading on different compounds/formulations used for . In the instant case, the species are structurally different, i.e., small peptides, small molecules or antibodies; and these species are not obvious variants of each other.
The requirement is still deemed proper and is therefore made FINAL.
The species of the Composition Administered and Treatment, therefore claims 1, 2, 5-12, 19, and 20 which read on the elected species has been considered.
Claims 3, 4, and 13-18 are 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. Election was made without traverse in the reply filed on July 17, 2026.
Priority
This application claims the benefit of U.S. Provisional Application No. 63/472,637 filed June 13, 2023 and U.S. Provisional Application No. 63/621,814 filed January 17, 2024.
Status of Claims
Claims 1-20 are pending.
Claims 3, 4, and 13-18 are withdrawn for further consideration.
Claims 1, 2, 5-12, 19, and 20 are currently examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on November 14, 2024 was reviewed by the Examiner.
The listing of references under the Non-Patent Documents in the IDS has the first author name misspelled in row 15. The information disclosure statement filed 11/14/2024 fails to comply with 37 CFR 1.98(a)(1), which requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement. The information disclosure statement has been placed in the application file, but the information referred to therein has not been considered.
Claim Interpretation
The election of species of Micafungin read on claims 1, 2, 7, 8, and 19.
The election of anti-viral agent of Palivizumab read on claims 7, 9, 10, 11, and 20.
The election of specific viral infection for treatment of respiratory syncytial virus (RSV) read on claims 1-12.
BRI of claims 1 and 8 is a method of treating or preventing a viral infection respiratory syncytial virus (RSV). The claims are given construction in view of the definition the terms "prevent" and "preventing" include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity is reduced (see page 7, line 26-28). The terms "treat" and "treating" are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression. (see page 7, line 29-31).
BRI of claim 5 is a method of treating or preventing a viral infection, wherein the viral infection is a positive-sense virus or negative-sense RNA virus. This claim is given construction in view of the definition the viral infection is a positive-sense or negative-sense RNA virus, non-segmented negative-sense (NNS) RNA virus such as respiratory syncytial virus (RSV), vesicular stomatitis virus (VSV), Nipah virus (NiV), variegated squirrel bornavirus (VSBV), coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), rabies virus (RABV), or ebola virus (EBOV) (see page 3, line 7-11); and specifically stated RSV has a negative-sense RNA genome encapsidated by nucleoproteins (see page 17, line 20-21).
The election of specific viral infection for treatment of respiratory syncytial virus (RSV) read on claim 5.
BRI of claim 12 is the method of treating or preventing a respiratory syncytial virus (RSV) infection comprising administering an effective amount micafungin or salt wherein the subject is diagnosed with RSV and a newborn less than 1 years old. This claim is given this construction in view of the definition of a "subject" refers to any animal, preferably a human patient, livestock, or domestic pet. In certain embodiments, the subject is a human subject less than 2, 12, or 16 years old or 2, 12, or 15 years old or older; the subject is a human subject 55 or 65 years old or older. In certain embodiments, the subject is a human subject greater than 55, 60, 65, or 70 years of age; the subject is an infant, e.g., from one month to two years of age; the subject is a human subject such as a child, e.g., from two to twelve years of age. In certain embodiments, the subject is a human subject such as an adolescent, e.g., from twelve to sixteen years of age; the subject is a human subject sixteen years of age or older (see page 7, line 13-21); the method comprises preventing very severe RSV or other infection in an infant or pediatric subject or immune compromised patient or elderly patient in need thereof; the subject is a human patient, e.g., newborn less than 1 years old; the human subject experienced, is at risk of, or diagnosed with premature birth, chronic lung disease (CLD), congenital heart disease, compromised immunity, or at an age younger than 6 weeks old; the subject is a human patient, e.g., newborn less than 1 years old. In certain embodiments, the subject is more than 1 years old; the compound is administered at birth (see page 10, line 20-27).
Claim Objections
Claim 1 objected to because of the following informalities: word “of” missing after the claim statement “A method of treating or preventing a viral infection comprising administering an effective amount”.
Appropriate correction is required.
Claim 12 objected to because of the following informalities: the claim statement “a newborn less than 1 years old” is grammatically incorrect in standard English.
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.
First rejection – Scope of Enablement
Claims 1, 2, and 5 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 treating RSV, does not reasonably provide enablement for preventing all viral infection. 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 Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
The nature of the invention and the breadth of the claims
The claims are drawn to a method of treating or preventing a viral infection comprising administering an effective amount an RNA-dependent RNA Polymerase (RdRP) inhibitory compound, derivative, or salt thereof to a subject in need thereof, wherein the compound is selected from: micafungin. Embodiments of the instant specification disclose method comprises preventing very severe RSV or other infection in an infant or pediatric subject or immune compromised patient or elderly patient in need thereof. In certain embodiments, the subject is a human patient, e.g., newborn less than 1 years old. In certain embodiments, the human subject experienced, is at risk of, or diagnosed with premature birth, chronic lung disease (CLD), congenital heart disease, compromised immunity, or at an age younger than 6 weeks old. In certain embodiments, the subject is a human patient (see page 10, line 20-25). The specification states, in certain embodiment, this disclosure relates to methods of treating or preventing a respiratory syncytial virus (RSV) infection or other viral infection comprising administering an effective amount of micafungin (see page 12, line 3-5).
However, prevention as claimed reads on administering effective amount an RNA-dependent RNA Polymerase (RdRP) inhibitory compound, i.e., micafungin to any individual with a viral infection. The specification does not teach a method of prevention of all/any viral infection for a patient in need, using micafungin as claimed. Accordingly, the claim 1 and dependent claims are unduly broad with respect to a method of preventing a viral infection.
The State of the Prior Art and The Level of Predictability in the Art
The state of the art at the time of filing did not recognize that micafungin could prevent a range of viral infections or related diseases. For instance, while Applicants are enabled for treating a subset of viral infections (see instant page 3, line 7-11) and prior art below, the art does not recognize that all viral infections can be prevented, let alone with an RNA-dependent RNA Polymerase (RdRP) inhibitory compound such as the instant micafungin. Although the instant specification states the method comprises preventing very severe RSV or other infection in an infant or pediatric subject or immune compromised patient or elderly patient in need thereof (see page 10, line 20-22), there is no prior art that teaches micafungin of claim 1 for prevention of viral infections. Prior art has investigated therapeutics for some viral infections, that suggest that therapeutic prevention might be possible someday but is presently not an option.
The Level of Skill in the Art
Practitioners in this art (clinicians, scientists) would presumably be highly skilled in the art for prevention or treatment of disease in a subject.
The Amount of Direction Provided by the Inventor
At the time of filing, no direction or guidance was presented in either the prior art or the instant specification that would enable one to administer micafungin to prevent a viral infection as claimed. The instant specification does not provide adequate guidance with regard to the actual treatment or prevention or the effective amount of the compound micafungin that is required to prevent any viral infection. Applicant’s limited disclosure is noted but is not sufficient to justify claiming prevention in a subject broadly. Absent a reasonable a priori expectation of success for using the micafungin as a method of prevention, one skilled in the art would have to extensively test the inhibitor compound on a representative number of subjects, determine dosing using different concentrations of the compound and ascertain a prevention standard.
The Presence or Absence of Working Examples
The instant specification provides no examples wherein micafungin is administered prior to the onset of a viral infection or a disease.
The quantity of experimentation necessary
As there are no working examples in either the instant specification nor the prior art, reasonable guidance with respect to preventing a viral infection through administration of a micafungin was limited. Consequently, one skilled in the art would be burdened with undue experimentation to determine the precise parameters and conditions necessary to effectively prevent a viral infection.
Therefore, in view of the Wands factors, as discussed above, Applicants fail to provide information sufficient to practice the claimed invention for the prevention of a viral infection or disease.
Second rejection – Written Description
Claims 7, 9-11 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.
Scope of the claims
The claims are drawn to compound administered comprising micafungin in combination with an anti-RSV agent palivizumab.
Actual Reduction to Practice
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the instant case, several embodiments of the invention were reduced to practice:
In certain embodiments, the recombinant RSV antibody is palivizumab (see page 10, line 1-2 and page 15, line 21-22). The specification states that in certain embodiments, the viral infection is respiratory syncytial virus (RSV) infection. In certain embodiments, the compound is administered in combination with an anti-RSV agent or an RSV-vaccine. In certain embodiments, the anti-RSV agent is ribavirin, lumicitabine, or YM-53403. In certain embodiments, the anti-RSV agent is a recombinant RSV antibody. In certain embodiments, the recombinant RSV antibody is palivizumab (see page 9, line 29-31, page 10, line 1-2), however, they are not represented in the reduction to practice. In addition, the specification fails to include a reduction to practice of a composition including both the active therapeutic agents.
Therefore, the instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
Sufficient relevant identifying characteristic
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination thereof.
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. MPEP 2163 (I)(A). The instant specification provides a Background that Palivizumab is a humanized monoclonal antibody targeting the fusion (F) protein of RSV. Palivizumab is indicated for use in high-risk children: preterm infants 35 weeks or less gestational age (GA), children with CLD of prematurity, and children with hemodynamically significant congenital heart disease (CHD) (see page 2, line 3-6). While the applicant details that the composition including micafungin and palivizumab could be used in the Methods of Use and Pharmaceutical Compositions and Kits section of the specification, the written description of improvement with treatment is not adequately supported with details or experimental examples with results.
Physical and/or chemical properties:
The data presented in the specification raise more questions about the physical properties of the genus than they answer. The data do not suggest the physical basis for the compound composition and therefore do not describe the binding affinity at the active site of the RSV polymerase. Understanding the physical basis for having anti-viral activity is critical to determining which of the compound that meet the inhibitor requirements of the genus also meet this additional functional requirement of the genus.
Functional characteristics when coupled with a known or disclosed correlation between function and structure:
The specification does not describe a general correlation between composition and structural coordinates for the claimed genus. Micafungin is a cyclic peptide derivative and palivizumab is a humanized monoclonal antibody. As a result, it is impossible to predict, based on the specification, how the combinatorial composition will affect the anti-viral activity relative to cytotoxicity.
Method of making the claimed invention:
Antiviral activity of micafungin and its derivatives, as well as palivizumab against RNA replication is well-known in the art. It is not disputed that one of ordinary skill in the art could synthesize or combine, albeit with route experimentation and optimization, the active compound provided that the composition is known. Where the specification fails to provide description is details in the composition to make. For example, the specific composition of each of the compounds, requirements for administration of the composition for treating/preventing RSV, etc. For all of the reasons presented above, one of ordinary skill in the art would not know which of the countless combinations of both the compounds that meet the composition requirements of the claims would also have specific therapeutic efficacy with expected anti-viral activity. The lack of written description about the method of treatment makes knowing if the inventor has possession of the composition at the time of filing inconclusive.
Conclusion:
For these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 2, and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Shen et. al. (“Antiviral activity and mechanism of the antifungal drug, anidulafungin, suggesting its potential to promote treatment of viral diseases”; Shu Shen, Yaxian Zhang, Zhiyun Yin, Qiong Zhu, Jingyuan Zhang, Tiantian Wang, Yaohui Fang, Xiaoli Wu, Yuan Bai, Shiyu Dai, Xijia Liu, Jiayin Jin, Shuang Tang, Jia Liu, Manli Wang, Yu Guo, and Fei Deng; BMC Medicine, 20:359, page 1-19, published October 21, 2022).
Shen et. al. teaches anti-viral effects of echinocandins and their clinical importance for patients with infection of viruses, which may promote therapeutic strategies as well as treatments and improve outcomes pertaining to various viral and fungal diseases (see Abstract, paragraph 4). Shen et. al. screened an FDA-approved drug library for chemicals against severe fever with thrombocytopenia syndrome disease (SFTS), caused by the novel tick-borne SFTS virus (SFTSV) infection, and six drugs were identified as effective inhibitors of the entire SFTSV infection process in vitro; of these, anidulafungin, the anti-fungal drug belonging to the echinocandin family, was found to inhibit SFTSV infection at the virus entry stage (see page 2, right col, paragraph 3).
Regarding claim 1: Shen et. al. discloses about the possible therapeutic strategies as well as treatments and improve outcomes pertaining to various viral and fungal diseases, regarding the use of anidulafungin as well as other echinocandins at clinical levels (page 3, left col, paragraph 1). Since anidulafungin is a member of the echinocandin family, Shen et. al. further investigated the effects of micafungin ….. analog of anidulafungin, on SFTSV infection (see page 7, left col, paragraph 2). Shen et. al. teaches micafungin was the most studied echinocandin for exerting effective antiviral activity against different viruses (see page 16, right col – page 17, left col, paragraph 1). Shen et. al. summarizes micafungin suppresses enterovirus 71 infection by affecting intracellular events, IRES-dependent translation, and polyprotein processing; inhibits chikungunya virus infection by limiting viral replication, release, and cell-to-cell transmission; and reduces the infection efficiencies of dengue virus (DENV) by disrupting virus binding, entry, and stability (see page 17, left col, paragraph 1). Shen et. al. further teaches molecular docking analyses and in vitro experiments identified micafungin …as potential inhibitors of SARS-CoV-2 (see page 17, left col, paragraph 1). Shen et. al. identified antiviral drugs to inhibit severe fever with thrombocytopenia syndrome disease (SFTS), caused by the novel tick-borne SFTS virus (SFTSV) (see Abstract). Regarding SFTSV, Shen et. al. further summarizes the genome of SFTSV contains three RNA segments: L, M, and S, which encode the RNAdependent RNA polymerase (RdRp), the glycoprotein (GP), and the nucleoprotein (NP) and the nonstructural protein (NSs), respectively (see page 2, right col, paragraph 2). Shen et. al. elaborates SFTSV genome RNA replication occurs in the cytosol, which is initiated de novo by SFTSV RdRp and then synthesizes the antigenomic complementary RNA (cRNA), genomic viral RNA (vRNA), and capped, mostly non-polyadenylated viral mRNA (see page 2, right col, paragraph 2). This is in direct correlation with the instantly claimed invention which specifies the RNA-dependent RNA Polymerase (RdRP) of RSV is needed for replication and transcription (see instant Specification, page 17, line 8-9); the L protein, the catalytic core of the RNA-dependent RNA Polymerase (RdRP), is usually a primary target against viral infection (see instant Specification, page 17, line 23-24).
Examiner’s Note: SFTSV belongs to negative-strand RNA viruses similar to instantly claimed Respiratory syncytial virus (RSV). Additionally, the catalytic core of the RNA-dependent RNA Polymerase (RdRP) of SFTSV as primary target against viral infection is also same as RSV.
Shen et. al. discloses the use of chemical compounds, including micafungin …were purchased from Selleck Chemicals (Houston, TX, USA) (see page 3, right col, paragraph 2). It is thus a salt derivative of micafungin. This is in direct correlation with the instant claim which states “inhibitory compound, derivative, or salt thereof to a subject in need thereof, wherein the compound is selected from: micafungin” (see instant claim 1).
Shen et. al. further teaches that micafungin was administered to a patient with COVID-19 accompanied by candidemia and improved the outcome of the patient administered tocilizumab (see page 17, right col, paragraph 2). Antiviral strategies and specific drugs could be designed and developed by targeting these steps so as to inhibit SFTSV infection and prevent the virus spreading (see page 2, right col, paragraph 2).
Examiner’s Note: It is known in the art about the use of monoclonal antibody (mAb) for treating anti-viral infection (see Reichert editorial review). Reichert provides review of the clinical development of several monoclonal antibody (mAb) … six mAbs, rituximab, trastuzumab, infliximab, daclizumab, basiliximab and palivizumab, were approved by the US Food and Drug Administration (FDA); these therapeutics represented important advances in the treatment of serious or life-threatening diseases including lymphoma, breast cancer, Crohn disease, prevention of kidney transplant rejection and prevention of respiratory syncytial viral infection; with five mAbs currently undergoing FDA review for anticancer, immunological
and antiviral indications, and one under review for treatment of bone disorders, the candidates in review are ofatumumab, tocilizumab… (see left col, paragraph 1).
It is to be noted that in the instantly claimed invention, micafungin is administered in combination with palivizumab.
Based on the study, Shen et. al. proposes that investigating the potential therapeutic
effects of echinocandins, such as anidulafungin and micafungin, in treating SFTS and other infectious viral diseases, may promote the design of therapeutic strategies and help improve the treatment and outcomes of patients suffering from serious viral and fungal infections (see page 17, right col, paragraph 3).
Based on the teachings of Shen et. al. above, it would have been obvious to utilize the antiviral activity of enchinocandins, more specifically micafungin could be administered along with monoclonal antibody for treatment of viral infection. It would have been obvious to target the viral RNA-dependent RNA polymerase as disclosed by Shen et. al., i.e., preferably echinocandins may be developed as drugs that act against broad-spectrum viruses (see page 17, left col, paragraph 1).
Therefore, before the effective filing date of the claimed invention, the claimed invention was prima facie obvious to the artisan of the ordinary skill. It would have been prima facie obvious for one of ordinary skill in the art to modify the teachings of Shen et. al. with the expectation to achieve therapeutic composition suitable for treating or preventing a viral infection.
Regarding claim 2: Shen et. al. teaches Micafungin was the most studied echinocandin for exerting effective antiviral activity against different viruses (see page 16, right col – page 17, left col, paragraph 1); and discloses reagents used as chemical compounds, including micafungin (see page 3, right col, paragraph 2).
Regarding claim 5: Shen et. al. teaches effects of echinocandins, such as anidulafungin and micafungin, in treating SFTS and other infectious viral diseases, may promote the design of therapeutic strategies and help improve the treatment and outcomes of patients suffering from serious viral and fungal infections (see page 17, right col, paragraph 3); micafungin suppresses enterovirus 71 infection by affecting intracellular events, IRES-dependent translation, and polyprotein processing; inhibits chikungunya virus infection by limiting viral replication, release, and cell-to-cell transmission; and reduces the infection efficiencies of dengue virus (DENV) by disrupting virus binding, entry, and stability (see page 17, left col, paragraph 1).
Claims 6-12, 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Shen et. al. (“Antiviral activity and mechanism of the antifungal drug, anidulafungin, suggesting its potential to promote treatment of viral diseases”; Shu Shen, Yaxian Zhang, Zhiyun Yin, Qiong Zhu, Jingyuan Zhang, Tiantian Wang, Yaohui Fang, Xiaoli Wu, Yuan Bai, Shiyu Dai, Xijia Liu, Jiayin Jin, Shuang Tang, Jia Liu, Manli Wang, Yu Guo, and Fei Deng; BMC Medicine, 20:359, page 1-19, published October 21, 2022) as previously applied to claims 1, 2, 5, and 19; in view of Nakajima et. al. (“Antiviral Activity of Micafungin and Its Derivatives against SARS-CoV-2 RNA Replication”; Shogo Nakajima, Hirofumi Ohashi, Daisuke Akazawa, Shiho Torii, Rigel Suzuki, Takasuke Fukuhara and Koichi Watashi; Viruses 2023, 15, 452; published February 6, 2023); and further in view of Turner et. al (“Respiratory syncytial virus: current and emerging treatment options”; Tiffany L Turner, Benjamin T Kopp, Grace Paul, Lindsay C Landgrave, Don Hayes Jr, Rohan Thompson; ClinicoEconomics and Outcomes Research 2014:6 217–225; published April 25, 2014).
The teachings of Shen et. al. are discussed above. Although Shen et. al. teaches about echinocandins’ antiviral activity on (-) ssRNA virus including micafungin, however, the experimental results are mostly focused on micafungin derivative.
Nakajima et. al. teaches about anti-viral activity of micafungin; focused on micafungin …and analyzed their antiviral activities against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (see Abstract). Nakajima et. al. discloses Micafungin, Mi-2, and Mi-5 were suggested to inhibit the intracellular virus replication process; additionally, these compounds were active against SARS-CoV-2 variants… and a variant resistant to casirivimab/imdevimab
antibody cocktail (see Abstract). Nakajima et. al. teaches that analogues that target viral polymerases show broad spectrum antiviral effects; they were developed as drug candidates against viruses including ebola virus, hepatitis C viruses, and respiratory syncytia virus, before the COVID-19 pandemic (page 1, paragraph 1). Nakajima et. al. demonstrated Micafungin (MCFG) and its derivatives inhibit SARS-CoV-2 replication; and the data suggest that MCFG, Mi-2, and Mi-5 (micafungin derivatives) target virus replication, rather than the process for viral entry (see 3.2, page 5, paragraph 1).
Examiner’s Note: It is known in the art about the similarities and differences between negative (-) ssRNA and positive (+) ssRNA viruses. Liang provides a detailed review of structures of Mononegavirales (nonsegmented negative-sense RNA viruses) which includes rabies virus (RABV), human respiratory syncytial virus (HRSV), and Ebola virus (EBOV) (see Abstract). Viral polymerases have been attractive and major antiviral therapeutic targets (see Abstract). Liang further teaches Mononegavirales use the negative-sense genomes as the templates for the following two distinct viral RNA synthesis processes: (i) transcription to generate 5 to 10
discrete 5’ capped, methylated and 3’ polyadenylated viral mRNAs; and (ii) replication
to produce complementary positive-sense antigenomes that act as templates for
progeny negative-sense genomes (see in Fig. 1 [shown below], page 3, paragraph one), where before translation occurs, it must be transcribed into positive sense RNA.
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714
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Liang teaches viral polymerases have been attractive and major antiviral therapeutic
targets, as seen in multiple drug discovery successes in various viral pathogens,
including HIV-1, hepatitis C virus (HCV), and hepatitis B virus; the structures of the Mononegavirales polymerases including the L protein in complex with its cofactor P protein of VSV, RABV, HRSV, HMPV, and HPIV, reveal three conformations poised for initiation and elongation of RNA synthesis; and collectively, the structures of the Mononegavirales
polymerases provide significant advances into understanding the molecular
architectures, interrelationship, the inhibitors, and the evolutionary implications of the
Mononegavirales polymerases (see Conclusion, page 15-16).
It would have been obvious to combine the teachings of Shen et. al., and Nakajima et. al., before the effective filing date of the claimed invention utilizing the teaching known in the art, and considering the similarities in therapeutic target utilized, it would have been reasonable to use micafungin for antiviral activity against (-) ssRNA like RSV viral infection. One of ordinary skill in the art would have been motivated to do so with an expectation to succeed in preparing potent antiviral compounds and micafungin derivatives may be useful not only for developing anti-SARS-CoV-2 drugs but also as broad-spectrum antiviral drugs (see Nakajima et. al. page 7-8). Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
However, Nakajima et. al. is silent about the use of monoclonal antibody in combination with micafungin for the treatment or prevention of viral infection, more specifically, RSV.
Regarding claim 6: Turner et. al. discusses the current and evolving trends in RSV treatment for infants and children (see Abstract). Turner et. al. teaches Palivizumab is a humanized monoclonal antibody specifically targeting one of the RSV proteins (see page 219, right col, paragraph 6). Turner at. al. summarizes while palivizumab has been extensively studied in the setting of RSV prophylaxis, limited literature is available addressing its use for treatment; one systematic review evaluated the outcomes when palivizumab was used for the treatment of both upper and lower respiratory tract infections; another study evaluated 31 pediatric patients who received IV palivizumab for the treatment of RSV, patient illnesses ranged from complex congenital heart disease to hematopoietic stem cell transplant, and greater than three-fourths of patients who received palivizumab also received ribavirin therapy (see page 220, paragraph 1-2).
Turner et. al. also teaches ribavirin inhibits replication of both RNA and DNA viruses, including RSV; this inhibition is achieved by direct (interference with RNA capping, polymerase inhibition, lethal mutagenesis) (see Therapeutic Options, paragraph 1, page 221) [Examiner’s Note: this mechanism of inhibition is in direct correlation with the mechanism by which micafungin or micafungin derivatives targets (-) ssRNA virus]. Turner et. al. teaches ribavirin can be administered intravenously, orally, and by aerosolization; often been given in combination with IV immunoglobulin (see Therapeutic Options, paragraph 1, page 221). However, Turner et. al. also points out concerns for potential teratogenicity of inhaled ribavirin particles, so safety measures are warranted, and subsequent monitoring of pulmonary function and hematologic parameters is important (see Therapeutic Options, paragraph 1, page 221).
It would have been obvious to combine the teachings of Shen et. al., Nakajima et. al., and Turner et. al. before the effective filing date of the claimed invention by utilizing the therapeutic antiviral effect of micafungin in combination with monoclonal antibody palivizumab and arrive at the instantly claimed invention. One of ordinary skill in the art would have been motivated to utilize the teachings of Turner et. al. that the safety concerns often overshadow the potential benefits of ribavirin, limiting its routine clinical use (see page 221, right col, paragraph 1) and maintain the mainstay of therapy for RSV infection is prevention with palivizumab (see page 223, paragraph 2); and replace ribavirin with antiviral effective therapeutic compound - micafungin as taught by Shen et. al. and Nakajima et. al. with a reasonable expectation of success because micafungin validates as potent inhibitors of viral replication (taught above). Thus, one skilled in the art can predict antiviral effect of micafungin targeting RSV polymerase (Shen et. al.) in combination with monoclonal antibody palivizumab administered for better management of RSV infection with an expectation to succeed in developing therapies that dampen viral infection and disease progression (Turner et. al.).
Regarding claims 7, 9 and 20: Shen et. al. teaches micafungin was administered accompanied by candidemia and improved the outcome of the patient administered tocilizumab (see page 17, right col, paragraph 2) [Examiner’s Note: tocilizumab has comparable antiviral activity against (-) ssRNA viruses, see Reichert]. Turner et. al. teaches Palivizumab is a humanized monoclonal antibody specifically targeting one of the RSV proteins (see page 219, right col, paragraph 6).
It would have been obvious to combine the teachings of Shen et. al., and Turner et. al., before the effective filing date of the claimed invention utilizing combination of micafungin with monoclonal antibody, more specifically palivizumab, administered for better management of RSV infection.
Regarding claims 8 and 19: Shen et. al. and Nakajima et. al. use micafungin and its derivatives from Selleck Chemicals (see Shen et. al. Methods, Antibodies and Reagents; and Nakajima et. al. Materials and Methods, Compounds). The compounds are salt derivates of micafungin.
Regarding claims 10 and 11: Turner et. al. teaches use of recombinant RSV antibody, as palivizumab.
Regarding claim 12: Turner et. al. teaches respiratory syncytial virus (RSV) is an important respiratory pathogen in infants and children worldwide; RSV typically causes mild upper respiratory infections, it frequently causes severe morbidity and mortality, especially in premature infants and children with other chronic diseases (see Abstract).
Based on the above established facts from the cited prior art, it appears that all the claimed elements, i.e., applicants’ individual components in the composition and their use as antiviral therapy, were known in the prior art, and one skilled person in the art could have combined the elements as claimed by known relationships, with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art.
The motivation to modify and combine the art can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. See MPEP 2144.07. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by taking the advantage of the teaching of the above cited references and to make the instantly claimed antiviral therapeutic composition with a reasonable expectation of success for treating or preventing a viral infection.
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Prior Art Cited but not Referenced
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Reichert (Editorial - Letter from the Editor; mAbs 1:3, 189-189; May/June 2009)
Liang (Structures of the Mononegavirales Polymerases; Virol 94:e00175-20; published October 27, 2020)
Tian et. al. (RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic; Lei Tian, Taotao Qiang, Chengyuan Liang, Xiaodong Ren, Minyi Jia, Jiayun Zhang, Jingyi Li, Minge Wan, Xin YuWen, Han Li, Wenqiang Cao, Hong Liu; European Journal of Medicinal Chemistry 213(2021)113201; published January 21, 2021).
Conclusion
No claim is allowed.
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/KOYELI BANERJEE/Examiner, Art Unit 1658
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
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