DETAILED ACTION
This office action is in response to applicant’s filing dated October 29, 2025.
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 – 12 and 15 – 20 are pending in the instant application. Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on October 29, 2025 are acknowledged.
Claims under consideration in the instant office action are claims 1 – 12 and 15 – 20.
Objections and/or Rejections and Response to Arguments
Applicants' arguments, filed on October 29, 2025, have been fully considered but they are not deemed to be persuasive. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Maintained Objections and/or Rejections
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 – 11 and 16 – 18 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 and preventing viral infection caused by HIV virus and SARS-CoV-2 with compound of formula (I) (Q-VE-OPh), does not reasonably provide enablement for treatment or prevention of any viral infection with the compound of instant invention. 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. This is a scope of enablement rejection.
The present claims relate to the treatment or prevention of viral infection caused by any virus with the compound Q-VE-OPh, which is defined as caspase inhibitor (https://www.creative-enzymes.com/product/qvdoph-negative-control_2667.html).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls.1986) at 547 the court recited eight factors:
the quantity of experimentation necessary,
the amount of direction or guidance provided,
the presence or absence of working examples,
the nature of the invention,
the state of the prior art,
the relative skill of those in the art,
the predictability of the art, and
the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. Nature of the invention and the Breadth of the claims.
The invention is drawn to a method for treatment of any viral infection with caspase inhibitor Q-VE-OPh. The breadth of the claims is extensive.
First, applicants claim the method of treating and preventing viral infections, which encompasses all types of viral infections:
- Upper respiratory infections include sore throat, sinusitis, and the common cold. Other viral respiratory infections include influenza, pneumonia, and coronaviruses, including SARS-CoV-2 (the virus that causes COVID-19).
- Gastrointestinal tract: Infections of the gastrointestinal tract, such as gastroenteritis, are commonly caused by viruses, such as noroviruses and rotaviruses.
- Liver: These infections result in hepatitis.
- Nervous system: Some viruses, such as the rabies virus and the West Nile virus, infect the brain, causing encephalitis. Others infect the layers of tissue that cover the brain and spinal cord (meninges), causing meningitis.
- Skin: Viral infections that affect only the skin sometimes result in warts or other blemishes. Many viruses that affect other parts of the body, such as chickenpox, also cause a rash.
- Placenta and fetus: Some viruses, such as the Zika virus, the rubella virus, and cytomegalovirus, can infect the placenta and fetus in pregnant women.
Some viruses typically affect many body systems. Such viruses include enteroviruses (such as coxsackieviruses and echoviruses) and cytomegaloviruses.
Applicant proposes to treat all of the above conditions with Q-VE-OPh.
2. Relative skill of those in the art.
The level of ordinary skill in the art may be found by inquiring into: (1) the type of problems encountered in the art; (2) prior art solutions to those problems; (3) the rapidity with which innovations are made; (4) the sophistication of the technology; and (5) the education level of active workers in the field. Custom Accessories, Inc., 807 F.2d at 962. All of those factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed.Cir.1983).
Based on the typical education level of active workers in the fields of Medicinal chemistry, biology, biochemistry, and pharmacology, as well as the high degree of sophistication required to solve problems encountered in the art, the Examiner finds that a person of ordinary skill in the art would have at least a college degree in one of the fields identified above and at least four years of work experience; i.e. a masters or doctorate level scientist.
3. The predictability or unpredictability of the art and the state of the prior art.
The instant claimed invention is highly unpredictable as discussed below:
viral infections in general encompasses infections caused by different viruses. It is noted, that the various diseases and disorders encompassed by the broad category of viral infections have different causes and, molecular mechanisms which contribute to the final pathology and clinical manifestations of the disease. There is no common mechanism by which all viral diseases arise. Accordingly, treatments for these diseases are normally tailored to the particular type of disease as there is no, and there can be no “magic bullet” against all viral infections or disorders in general. The pathogenesis of these diseases is complex and different.
Accordingly, the unpredictability of treating any of the viral infections with Q-VE-OPh is very high. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art, the examiner cites: Callus et al (Cell Death and Differentiation (2007) 14, 73–78), Poreba et al. (Cold Spring Harb Perspect Biol 2013;5:a008680), and Dhani et al (Cell Death and Disease (2021) 12:949).
With regard to unpredictability Callus et al., cited for evidentiary purposes, teaches: synthetic caspase inhibitors have been developed both as research tools, and with the hope that they may eventually be used to prevent cell death in the clinic. However, inhibitors that are specific for caspases are more useful for research, and only these could be used in the clinic (page 76, left column, 1st paragraph). Until the effects of synthetic caspase inhibitors are confirmed in cells and ultimately in vivo, caution should be exercised when assigning an inhibitor’s caspase specific it solely on in vitro determined Kis (inhibitory constant), particularly when the Kis are derived from cleavage assays that utilize non-physiological peptide-based substrates (page 76, right column, 4th paragraph). Ideally, when peptidic caspase inhibitors are used, control experiments should be performed with a compound with the same warhead group, but with a glutamic acid residue in place of the aspartic acid (P1) residue (page 77, right column, 1st paragraph).
Furthermore, with regard to unpredictability Poreba et al., cited for evidentiary purposes, teaches: various types of synthetic inhibitors have been described in the literature, including peptides. The guiding principle for many of these studies has been to generate therapeutic leads to modulate apoptotic and inflammatory pathways in disease. The main feature for efficient proteolysis is that caspases require an aspartate residue at P1 and recognize at least four amino acid residues to the left of the cleavage site. As in the case of substrates, truncation of a tetrapeptide to a tripeptide or dipeptide leads to a dramatic decrease in inhibitor peptide-based activity (page 10, “warheads”).
Poreba et al., further notices: unfortunately, most of these inhibitors cannot play therapeutic roles because of their toxic metabolites (page 12, “therapeutic leads”). Summarizing the review Poreba et al., conclude: the explosion of synthetic caspase substrates and inhibitors over the last few years has revealed the promise of defining the fundamental properties of caspases as enzymes, their role in promoting apoptosis and inflammation, and provided several excellent scaffolds for therapeutic leads. More selective inhibitors and a better understanding of the final outcomes of caspase inhibition in human disease are needed (page 16, “conclusion”).
Moreover, with regard to unpredictability Dhani et al., in a later dated reference, teaches: multiple caspase inhibitors have been designed and synthesized as a potential therapeutic tool for the treatment of cell death-related pathologies. However, only a few have progressed to clinical trials because of the consistent challenges faced amongst the different types of caspase inhibitors used for the treatment of the various pathologies, namely an inadequate efficacy, poor target specificity, or adverse side effects. Importantly, a large proportion of this failure lies in the lack of understanding various caspase functions. To overcome the current challenges, further studies on understanding caspase function in a disease model is a fundamental requirement to effectively develop their inhibitors as a treatment for the different pathologies (abstract).
Summarizing the review Dhani et al., conclude: nevertheless, the accumulated preclinical studies provide a lead for further investigations in understanding the exact roles of caspases (apoptotic/nonapoptotic and inflammatory/non-inflammatory), and alternate caspase-independent responses in disease states which importantly, will provide a better approach for targeting caspases and therapeutic advantage (page 9 “conclusion”).
These articles plainly demonstrate that the art of developing and testing therapies to treat any and all types of viral infection or with compounds of instant claims is unpredictable. More generally, 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).
4. Amount of guidance/Existence of working examples.
The instant claims read on treatment or prevention of any viral infection with the compound of formula Q-VE-OPh. The specification fails to provide adequate support for effectively treating or preventing any viral infection in a patient, except for infection caused by HIV virus and SARS-CoV-2. Applicant fails to provide any information sufficient to practice the claimed invention, absent undue experimentation. Although specification provides a general directions or guidance on dosage and route of administration e.g.: “for example, it is possible to administer from 15 to 50 mg/kg body weight of compound…” (page 19, lines 30 – 31) ; “…the antiviral composition of the invention, can be administered by the enteral, parenteral (intravenous, intramuscular or subcutaneous), transcutaneous…route (page 19, lines 7 – 8)” necessary to treat viral infection, or prevent disease progression to severity by administering antiviral composition comprising compound Q-VE-OPh, however, applicants fail to disclose the treatment of viral infections other than those caused by HIV virus and SARS-CoV-2 with said antiviral composition. Absence of working examples is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164.
5. The quantity of experimentation necessary.
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that antiviral composition comprising compound Q-VE-OPh is useful in the prevention or treatment of all viral diseases. Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and ‘patent protection’ is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (42 USPQ 2d 1001, Fed. Circuit 1997). As noted above, none of the experimentation provided is drawn to the treatment of a viral infection other than caused by HIV virus and SARS-CoV-2. Thus, the specification fails to provide clear and convincing evidence in sufficient support for practicing the invention as claimed. Thus, factors such as “sufficient working examples” “guidance’ and “predictability”, etc. have been demonstrated to be sufficiently lacking in the instantly claimed methods. In view of the breadth of the claims, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate with the scope of the claims.
Therefore, in view of the Wands factors discussed above, to practice the claimed invention herein, a person of ordinary skill in the art would have to engage in undue experimentation to test which diseases can be treated by compositions encompassed by the instant claims, with no assurance of success. Thus, rejection of claims 1 – 11 and 16 – 18 under 35 U.S.C. §112 (a), is deemed proper.
Response to Arguments
Applicant argues:
- in the present invention the use of Q-VE-OPh in the prophylaxis and/or treatment of a viral infection is not only illustrated for HIV infection (example 1) but also for SARS-CoV2 infection (example 2), which illustrates that Q-VE-OPh can be used in the prophylaxis and/or the treatment of a viral infection with two very different types of viruses, namely retroviruses and coronaviruses. These types of viruses are so different that it is difficult to doubt that Q-VE-OPh cannot be used in the prophylaxis and/or the treatment of any virus.
Examiner’s response:
Applicant's arguments have been fully considered but they are not persuasive because: as set forth above, although Applicant presented experimental data of therapeutic effect of compound of the invention on HIV infection (example 1) and SARS-CoV2 infection, the presented data do not provide enough evidence to enable treatment of any virus with the claimed compound. Treatment of virus in general is not enabled. Examiner emphasizes, treatments for these diseases are normally tailored to the particular type of disease as there is no, and there can be no “magic bullet” against all viral infections or disorders in general. The pathogenesis of these diseases is complex and different (see the rejection section above). Thus, according to In re Wands factors (see above): the claims is broad in scope; the nature of the invention is sophisticated; the state of the prior art does not establish any drug to treat all viruses; the level of skill is high; the level of unpredictability is high; the direction provided by the inventor is limited to specification; the existence of working examples is limited to two species; and the quantity of experimentation includes testing the claimed composition against every virus.... Thus, based on the In re Wands factors, the claims lack enablement.
Therefore, Applicant arguments are not found persuasive and rejection of claims 1 – 11 and 16 – 18 under 35 U.S.C. 112(a) as not enabled for treating and preventing viral infection in general is maintained.
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 – 12 and 15 – 18 are rejected under 35 U.S.C. 103 as being unpatentable over Estaquier et al (US 2010/0298209 A1, cited in IDS, filed 11/11/2022, hereinafter Estaquier) in view of Southerland et al (Journal of Cell Death 2010:3 33–40, cited in IDS, filed 11/11/2022, hereinafter Southerland).
Instant claims are drawn to a method and composition for preventing or treating a respiratory viral infections such as coronavirus (SARS) or an infection caused by an HIV virus (e.g. lentivirus), where therapeutically effective amount of antiviral composition comprising compound of formula (I):
(i)
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114
306
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and
(ii) at least one antiviral and/or anti-inflammatory agent (e.g. transcriptase inhibitors), wherein said antiviral agent is different from (i), administered to a subject (ape or cat), where the composition reduces and/or inhibits viral replication, viral protein synthesis in a subject infected by said virus, and does not have any significant effect on cell death. The claimed antiviral composition further comprises one or more carrier(s), diluent(s) or adjuvant(s) or a combination thereof and formulated for the enteral, parenteral etc. route of administration. Estaquier teaches an antiviral composition and method of prophylaxis and/or treatment of viral infection caused by SARS virus or HIV virus (e.g. lentivirus) (page 7, [0107] and [0108], comprising administering to a subject (ape or cat) (page 6, [0081]) a therapeutically effective amount of said pharmaceutical composition comprising compound of formula (I):
(i)
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100
296
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, where B is dipeptide sequence, R1 and R2 are a hydrogen, R3 and R4 are fluoro, (e.g.
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85
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(Q-VD-OPh) (page 5, [0075]) and
(ii) at least one other antiviral agent (e.g. transcriptase inhibitors) (page 10, [0155]), where the composition reduces and/or inhibits viral replication, viral protein synthesis and inhibits an increase in cell death in an animal infected by said virus (page 19, claims 23, 24 and 26). Pharmaceutical composition, taught by Estaquier, further comprises one or more carrier(s), diluent(s) or adjuvant(s) or a combination thereof and formulated for the enteral, parenteral etc. route of administration (page 19, claims 29 and 30).
Estaquier does not teach a compound of formula (I) where B is particularly -Val-Glu- dipeptide sequence. However, Southerland teaches compounds:
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(Q-VD-OPh) and
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(Q-VE-OPh) (page 36, Fig. 1), where Q-VE-OPh substitutes a single amino acid, glutamic acid (E) for the aspartic acid (D) in Q-VD-OPh, thereby retaining the identical charge and molecular properties with only the addition of an extra –CH2 group (page 35, “results”). Southerland teaches that Q-VE-OPh exhibit similar properties as Q-VD-OPh on inhibiting the activation of caspases and cell apoptosis but requires much greater concentration to have inhibitory effect (page 36, left column). Southerland studied inhibitory effect of Q-VE-OPh and Q-VD-OPh on Jurkat human T leukemia cells.
Thus, Southerland teaches two closest homologues Q-VE-OPh and Q-VD-OPh having similar properties on inhibiting the activation of caspases and cell apoptosis. Estaquier teaches a method of prophylaxis and/or treatment of viral infection with pharmaceutical composition comprising compound of formula (I), such as Q-VD-OPh. Although prior art does not explicitly teach an antiviral activity of Q-VE-OPh, MPEP 2144.09(I) states: Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Hence, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to try to apply a known Q-VE-OPh compound to the method of treatment of viral infection caused by coronavirus or lentivirus since the prior art teaches its closest homolog Q-VD-OPh is an effective agent against these viruses. Thus, arriving to the claimed method and composition with the reasonable expectation of success.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Estaquier et al (US 2010/0298209 A1, cited in IDS, filed 11/11/2022) in view of Southerland et al (Journal of Cell Death 2010:3 33–40, cited in IDS, filed 11/11/2022) as applied to claims 1 – 12 and 15 – 18 above, and further in view of Wang et al (Cell Research (2020) 30:269–271, hereinafter Wang).
Estaquier and Southerland teach as discussed supra and are applied here in the same manner.
The cited references do not teach antiviral composition where antiviral agents viral RNA-dependent RNA polymerase modulators are nucleotide analogues (e.g. remdesivir). However, Wang teaches antiviral drug remdesivir as a promising drug against a wide array of RNA viruses (including SARS/MERS-CoV5) infection (page 269, 2nd paragraph).
Thus, viral RNA-dependent RNA polymerase modulator remdesivir is individually known as antiviral drug, effective against SARS virus. MPEP 2144.06 (I) states: It is generally obvious to combine two compositions, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose. In re Kerkhoven, 205 U.S.P.Q. 1069 (CCPA 1980). The idea for combining said compositions flows logically from their having been individually taught in the prior art. In re Crockett, 126 U.S.P.Q. 186, 188 (CCPA 1960). Accordingly, to establish obviousness in such fact situations it is NOT necessary that the motivation come explicitly from the reference itself (although the Examiner believes it does, as discussed supra). The natural presumption that two or more individually known antiviral agents would, when combined, provide a third composition also useful for treating viral infection caused by SARS virus, flows logically from each having been individually taught in the prior art.
Therefore, since prior art teaches an antiviral composition suitable to treat viral infection caused by SARS virus, where various known antiviral agents, discussed above, used individually or in combination, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to combine known in the art antiviral agents to arrive to the composition of claim 19 with the reasonable expectation of success.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Estaquier et al (US 2010/0298209 A1, cited in IDS, filed 11/11/2022) in view of Southerland et al (Journal of Cell Death 2010:3 33–40, cited in IDS, filed 11/11/2022) as applied to claims 1 – 12 and 15 – 18 above, and further in view of Zhang et al (Clinical Immunology 214 (2020) 108393, hereinafter Zhang).
Estaquier and Southerland teach as discussed supra and are applied here in the same manner.
The cited references do not teach antiviral composition where anti-inflammatory agent is an anti-IL6 receptor antibody (e.g. tocilizumab). However, Zhang teaches IL-6 inhibitor tocilizumab as an effective treatment in severe patients of COVID-19 (caused by SARS-CoV-2) (page 3, § 5.2).
Thus, IL-6 inhibitor tocilizumab is individually known as an anti-inflammatory agent, effective in treatment of patients of COVID-19 caused by SARS-CoV-2. MPEP 2144.06 (I) states: It is generally obvious to combine two compositions, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose. In re Kerkhoven, 205 U.S.P.Q. 1069 (CCPA 1980). The idea for combining said compositions flows logically from their having been individually taught in the prior art. In re Crockett, 126 U.S.P.Q. 186, 188 (CCPA 1960). Accordingly, to establish obviousness in such fact situations it is NOT necessary that the motivation come explicitly from the reference itself (although the Examiner believes it does, as discussed supra). The natural presumption that two or more individually known antiviral and anti-inflammatory agents would, when combined, provide a third composition also useful for treating viral infection accompanied by inflammation and caused by SARS virus, flows logically from each having been individually taught in the prior art.
Therefore, since prior art teaches an antiviral composition suitable to treat viral infection caused by SARS virus, where various known antiviral agents, discussed above, used in combination with an anti-inflammatory agent, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to combine known in the art antiviral and anti-inflammatory agent such as IL-6 inhibitor to arrive to the composition of claim 20 with the reasonable expectation of success.
Therefore, taking all together, taught by prior art, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues:
- Estaquier discloses a compound of formula (F) in which B is a peptide consisting of valine and aspartic acid (VD) namely Q-VD-OPh, Q-VE-OPh (compound of the present invention) corresponds to a compound of formula (F) in which B is a peptide consisting of valine and glutamic acid (VE). Nevertheless such a compound is not disclosed in Estaquier;
- the experimental data contained in the present application show that Q- VE-OPh has an antiviral effect illustrated on HIV (example 1) and on SARS- CoV2 (example 2) without having caspase inhibitory effect. In other words, Q- VE-OPh has an antiviral effect, and this effect is independent of caspase inhibition.
- Estaquier teaches that the compound Q-VD-OPh allows both inhibition of the apoptotic phenotype (caspase inhibition) and inhibition of viral replication (paragraph [0038] and examples). Other caspase-inhibiting compounds (Q-DEVD-OPh, Q-LEDH-OPh and Q-IETD-OPh are tested in Estaquier as comparative examples, comprise a glutamic acid (E). From the results presented at paragraph [0288], it is clear that only Q-VD-OPh is shown to be effective in inhibiting viral replication. Thus, the skilled person knows that the presence of glutamic acid (E) does not produce a compound that inhibits viral replication.
- Southerland discloses the use of Q-VE-OPh as a negative control for O- phenoxy-conjugated caspase inhibitors and thus Southerland clearly establishes that Q-VE-OPh has no caspase inhibitory activity.
- neither Estaquier nor Southerland provides any incentive for the one skilled in the art to develop a compound that has no caspase inhibitory activity, and contains a glutamic acid, as a viral replication inhibitor.
- Wang and Zhang were not cited for and do not make up for the basic deficiencies of the Estaquier/Southerland combination.
Examiner’s response:
Applicant's arguments have been fully considered but they are not persuasive because: as set forth above, Estaquier teaches compound Q-VD-OPh, which exhibit antiviral activity, via inhibiting viral replication. Southerland teaches compound Q-VE-OPh, where Q-VE-OPh substitutes a single amino acid, glutamic acid (E) for the aspartic acid (D) in Q-VD-OPh, thereby retaining the identical charge and molecular properties with only the addition of an extra –CH2 group (page 35, “results”). Southerland teaches that Q-VE-OPh exhibit similar properties as Q-VD-OPh on inhibiting the activation of caspases and cell apoptosis. Thus, compounds Q-VD-OPh and Q-VE-OPh are closest homologues, different in structure by –CH2- group. 2144.09(I) states: Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). In order to compare certain properties of two molecules, factual evidence should be presented. MPEP 2145 states: If a prima facie case of obviousness is established, the burden shifts to the applicant to come forward with arguments and/or evidence to rebut the prima facie case. See, e.g., In re Dillon, 919 F.2d 688, 692, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc). Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.").
Regarding Applicant arguments about comparative examples, described by Estaquier and comprising a glutamic acid (E), this argument is not persuasive, as comparative examples have a structure of tetrapeptide, and thus cannot exhibit similar properties as dipeptides Q-VD-OPh and Q-VE-OPh, due to significantly different structure and thus, different physical, chemical and pharmacological properties.
Regarding argument about references of Wang and Zhang, applied in the rejection of claims 19 and 20, the argument is not persuasive since claims are considered obvious in view of combined teachings of Estaquier, Southerland and Wang, as applied to claim 19, and combined teachings of Estaquier, Southerland and Zhang, as applied to claim 20.
Therefore, Applicant’s arguments are not persuasive and the rejection of claims: 1 – 12 and 15 – 18 as obvious over teaching of Estaquier and Southerland;
19 as obvious over teaching of Estaquier, Southerland and Wang; and
20 as obvious over teaching of Estaquier, Southerland and Zhang is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 – 7, 10, 12, 15 – 17, 19 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 10 of copending Application No. 18/730,927 in view of Estaquier et al (US 2010/0298209 A1, cited in IDS, filed 11/11/2022).
Instant claims are directed to a method and composition for preventing or treating a respiratory viral infections caused by SARS-CoV-2, where therapeutically effective amount of antiviral composition comprising compound of formula (I):
(i)
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and
(ii) at least one antiviral and/or anti-inflammatory agent, wherein said antiviral agent is different from (i), where the other antiviral agent can be a viral RNA-dependent RNA polymerase modulator and anti-inflammatory agent is monoclonal antibody, such as anti-IL6 receptor antibody. The instantly claimed composition reduces and/or inhibits viral replication, viral protein synthesis in a subject infected by said virus. The claimed antiviral composition further comprises one or more carrier(s), diluent(s) or adjuvant(s) or a combination thereof. The copending claims are directed to a method for preventing or treating a viral infections caused by SARS-CoV-2, where therapeutically effective amount of antiviral composition comprising compound of formula (I):
(i)
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(N-(2(quinolyl)-valyl-O-methylaspartyl-(2,6-difluorophenoxy)methyl ketone or QVDM-OPh) and
(ii) at least one additional therapeutic agent, such as compound of formula
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(QVE-OPh). The compound of formula (I) of copending claims is a closest homolog of the compound of instant claims in O-methylated form. MPEP 2144.09 (II) states: Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). The antiviral composition of copending claims further comprises antiviral and/or anti-inflammatory agent, where the other antiviral agent is a viral RNA-dependent RNA polymerase modulator, anti-inflammatory agent (monoclonal antibody) and pharmaceutically acceptable vehicle. The composition of copending claims reduces and/or inhibits viral replication and viral protein synthesis in a subject infected by said virus. Although instant claims are silent about the QVDM-OPh as an antiviral agent in the invented pharmaceutical composition, Estaquier teaches an antiviral composition or kit comprising:
compound of structure (I):
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(Q-VD-OPh (N-(2(quinolyl)valyl-aspartyl-(2,6-difluorophenoxy)methyl ketone), optionally in an O-methylated form (O-methylated form of QVD-OPh is a compound of formula (I) of copending claims), and
at least one other antiviral agent (abstract).
The antiviral composition, taught by Estaquier, is useful to treat viral infection caused by SARS virus ((page 18, claim 16).
Thus, taking into consideration the compositions and a method, taught by prior art, it would be prima facie obvious to one of ordinary skill in the art to arrive at the compositions and method of the instant claims with a reasonable expectation of success, since the prior art teaches the same or very similar drugs are useful in a method of treating viral infection caused by coronavirus (e.g. SARS or SARS-CoV-2).
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant argues:
- as claims have not been granted in that pending application, there is currently no obviousness type double patenting.
Examiner’s response:
Applicant's arguments have been fully considered but they are not persuasive because: as set forth above, copending application claims the same method (method for preventing or treating viral infections caused by SARS-CoV-2) with the same or similar composition (composition comprising QVE-OPh). Thus, instant claims and claims of copending application No. 18/730,927 are not patentably distinct. MPEP 804 states: If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent. In the instant case the provisional nonstatutory double patenting rejection is not the only rejection remaining in an application.
Therefore, Applicant’s arguments are not persuasive and the provisional rejection of claims 1 – 7, 10, 12, 15 – 17, 19 and 20 on the ground of nonstatutory double patenting over claims of copending Application No. 18/730,927 in view of Estaquier is maintained.
Conclusion
Claims 1 – 12 and 15 - 20 are rejected. No claim is allowed.
THIS ACTION IS MADE FINAL. 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.
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/E.V.V./Examiner, Art Unit 1691
/SAVITHA M RAO/Primary Examiner, Art Unit 1691