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 .
Status of Claims
The amended claims filed 09/23/2025 are acknowledged and entered.
Claim 10 has been cancelled,
Claims 1, 3-9, 11-15, and 19-24 are pending and examined on their merits.
Response to Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Objections
Specification - Withdrawn
The disclosure is objected to because of the following informalities:
a) The use of the term(s), e.g., Quil-A, Imject Alum, SpectraMax, M5e, Igepal CA-630, GraphPad Prism which are a trade name or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, and/or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Applicant has corrected the informalities in the substitute specification and the objection is withdrawn.
Claim Rejections - 35 USC § 101 - Withdrawn
1. The rejection of claim 10 under 35 U.S.C. 101 because of a lack of credible utility as it is wholly inconsistent with contemporary knowledge in the art is withdrawn in view of Applicant’s cancellation of claim 10
Claim Rejections - 35 USC § 112 - Withdrawn
The rejection of claim 10 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends (claim 1) is withdrawn in view of Applicant’s cancellation of claim 10.
Claim Rejections - 35 USC § 102 - Maintained
Applicant’s arguments with respect to the 35 USC 102 rejections of claims 1, 3-6, 9 and 11 have been fully considered and are not persuasive. Therefore, the rejections are maintained.
Claims 1, 3-6, 9 and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jacobs (IDS; WO 2015/134368 A2 published on September 11, 2015 (US patent 9,999,665 B2)) and evidenced by Dudek (Virology, 2006 Jan 5;344(1):230-9).
Claims 1, 3-6, 9 and 11 are drawn to a method for treating ocular disease caused by herpes simplex virus-1 (HSV-1) infection by administering to a subject a herpes simplex virus-2 (HSV-2) having a deletion of an HSV-2 glycoprotein D-encoding gene to treat the ocular disease, wherein the HSV-2 is phenotypically complemented with an HSV-1 glycoprotein D (gD) by propagating the HSV- 2 in a complementing cell expressing HSV-1 gD. The HSV-2 is a single cycle virus and a component of a pharmaceutical composition comprising an adjuvant. The ocular disease comprises blepharitis, conjunctivitis, keratitis, retinitis, scleritis. The deletion of the HSV-2 gD-encoding gene comprises a deletion of the entire HSV-2 gD gene. The subject is infected with HSV-1.
Jacobs teaches an isolated, recombinant HSV-2 virus having a deletion of an HSV-2 gD-encoding gene (hereinafter HSV-2 ΔgD) (claim 1) that can be used for treating or preventing an HSV-1 infection in a subject (claim 9). In addition, this deletion can encompass the entire gD gene as an HSV-2 gD-2 null virus was generated [00113]. The HSV-2 ΔgD virus is phenotypically complemented with an HSV-1 gD by propagating HSV-2 ΔgD virus in a complementing cell expressing HSV-1 gD [00112]. Jacobs also teaches pharmaceutical compositions comprising HSV-2 ΔgD virus that can include an adjuvant [0059]. In addition, Jacobs teaches a method of treating a disease caused by HSV-1 in a subject comprising administering the HSV-2 ΔgD virus and the diseases, caused by an HSV-1, include HSV keratitis and HSV retinitis [0064].
Dudek teaches a definition for single-cycle viruses as defective for one or more essential functions that can be involved in viral genome synthesis, assembly and release of viral particles, or re- infection of new host cells (figure 1). Since HSV-2 ΔgD has a deletion in the gD gene, which is essential for the viral life cycle (as evidenced by the need of propagating the HSV-2 ΔgD virus in a complementing cell expressing HSV-1 gD), HSV-2 ΔgD is inherently a single cycle virus.
The reference teachings anticipate the claimed invention.
4. Applicant’s arguments are as follows:
- (a) The cited references do not describe, nor make available, the claimed invention. Jacobs does not provide any showing that the vaccine is effective for ocular diseases. HSV keratitis and HSV retinitis are just mentioned in Jacobs as part of a list of all possible herpes diseases. It would not have been envisaged by a person of ordinary skill in the art from looking at the list of diseases in Jacobs that the vaccine would be effective for ocular diseases.
- (b) The ability of the single-cycle, HSV-2 having a deletion of glycoprotein D in the genome
(HSV-2 ΔgD), to provide both active and passive protection against primary lethal HSV-1 corneal disease was a surprising and unexpected result.
- (c) Dudek does not correct the deficiency in Jacobs. Dudek teaches a definition for single cycle
viruses. There is no mention of HSV ocular disease or infection in Dudek, and no
instruction or guidance on how to pursue a vaccine for HSV ocular disease.
Applicant’s arguments have been considered but are not persuasive. In response to
Applicant’s arguments:
- Regarding item (a), Jacob mentions in [0064] the following: “Also provided is a method of treating an HSV-2 infection in a subject or treating a disease caused by an HSV-1, HSV-2 or co-infection in a subject comprising administering…. (i) the recombinant HSV-2 virus as described herein; (ii) a virion thereof as described herein, (iii) the vaccine as described herein; (iv) a composition as described herein; or ( v) a pharmaceutical composition as described herein, in an amount effective to treat an HSV-1, HSV-2 or co-infection or treat a disease caused by an HSV-1, HSV-2 or co-infection in a subject…. In an embodiment of the methods, the disease caused by an HSV-1, HSV-2 or co-infection is herpes, oral herpes, herpes whitlow, genital herpes, eczema herpeticum, herpes gladiatorum, HSV keratitis, HSV retinitis, HSV encephalitis or HSV meningitis”. This is not a list of all possible diseases HSV-1 can cause but a partial list and thus the specification discloses a method of treating HSV keratitis and/or HSV retinitis in a subject. A person of ordinary skill in the art would have been able to "at once envisage" the use of the vaccine to treat an HSV ocular disease. Therefore, Jacobs anticipates the rejected claims 1, 3-6, 9 and 11.
- Regarding item (b), unexpected results are not applicable for rejections under 35 USC 102. The unexpected results will be addressed for rejections under 35 USC 103 as they are evidence of nonobviousness.
- Regarding item (c), Dudek is an evidentiary reference under 35 USC 102 cited only because it teaches a definition for single cycle viruses and thus, Jacobs’ HSV-2 ΔgD is inherently a single cycle virus. There is no mention in the rejection above that Dudek is cited for any other purpose related to treatment of an ocular disease. Therefore, this argument is not relevant to the fact that Jacobs anticipates the rejected claims 1, 3-6, 9 and 11 as discussed above.
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
Claim Rejections - 35 USC § 103 - Maintained
Claims 1 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Jacobs (WO 2015/134368 A2 published on September 11, 2015 (US patent 9,999,665 B2)) in view of Koganti (Microorganisms 2019, 7, 429, pages 1-16).
Claim 1 is discussed above.
Claims 7-8 are drawn to the subject receiving or having received an antiviral drug, wherein the antiviral drug comprises acyclovir.
Jacobs teachings have been discussed above.
Jacobs does not teach the addition of any antiviral treatment to the method of treating ocular disease caused by an HSV-1 infection using the HSV-2 ΔgD virus propagated in cells expressing HSV-1 gD.
Koganti teaches the current and emerging therapies for ocular HSV-1 infections (entire article) and in particular, Koganti teaches a list of approved nucleoside analogs for ocular HSV-1 including acyclovir (table 1).
One of ordinary skill in the art would have been motivated to use the teachings of Jacobs (a vaccine comprising HSV-2 ΔgD to treat ocular HSV-1 infections) in combination with Koganti (an antiviral drug, such as acyclovir, approved to treat ocular HSV-1 infections) as a form of combination therapy. That is, using multiple treatments or medications to address a specific medical condition with the goal to improve treatment efficacy, reduce side effects, and prevent resistance. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was 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.
6. Applicant’s arguments are as follows:
- (a) The ability of the single-cycle, HSV-2 having a deletion of glycoprotein D in the genome
(HSV-2 ΔgD), to provide both active and passive protection against primary lethal HSV-1 corneal disease was a surprising and unexpected result.
(1) Specification [17]: The unique immunology of the eye making systemic vaccination approaches ineffective for protecting against herpetic eye disease. The eye is a relatively immune privileged site and the ability of a vaccine to prevent ocular disease caused by HSV-1 differs from the ability of a vaccine to prevent vaginal or skin disease. The development of a vaccine to prevent ocular disease is also challenging because the eye is susceptible to immune mediated damage. Mechanisms understood to contribute to immune privilege include lack of direct lymphatic drainage, a blood-ocular barrier, as well as immunosuppressive and immunoregulatory responses. Additionally, the FcRn may preferentially transport immunoglobulin G (lgG) out of the eye into the systemic circulation, which could limit Ab-mediated protection. Further, because antibodies elicited by the HSV-2 ΔgD vaccine function primarily by activating Fc receptors to mediate antibody-dependent cellular cytotoxicity (ADCC), the ability of ADCC to protect the immune privileged eye was previously unknown.
(2) Specification [82]: Passive transfer of immune serum from HSV-2 ΔgD vaccinated mice was less effective against ocular disease compared to vaginal or skin disease. The reduction in efficacy with HSV-2 ΔgD immune serum in the prevention of ocular compared to
vaginal or skin disease, even when two doses were administered to address the relatively short
half-life (4-8 days) of murine IgG, likely reflects accumulation of less Ab in the eye, either
because of differences in vascular permeability and/or ability of the FcRn to pump Ab out of
the eye.
(3) The data in the instant application show that the HSV-2 ΔgD vaccine, which elicits antibodies that act primarily through their Fc component, provides significantly greater protection following a two-dose vaccine regimen than an adjuvanted glycoprotein D subunit vaccine (rgD-2) that elicits neutralizing, but not Fc receptor activating or complement binding responses, in a primary lethal ocular murine model. Further, only immune serum from HSV-2 ΔgD vaccinated mice provided significant protection in passive transfer studies. The significantly greater passive protection afforded by HSV-2 ΔgD persisted after controlling for total amount of HSV-specific IgG in the transferred serum. The antibodies elicited by HSV-2 ΔgD had significantly more C1q-binding and Fc gamma receptor-activation, a surrogate for ADCC function. These finding suggest that ADCC is protective in the eye and that non-neutralizing antibodies provide greater protection against primary ocular HSV disease than neutralizing antibodies.
- (b) To find obviousness, the Examiner must "identify a reason that would have prompted a person of ordinary skill in the art in the relevant field to combine the elements in the way the claimed new invention does." Id. Jacobs does not render the claims obvious since it is not
envisaged by a person of ordinary skill in the art from a review of Jacobs that a vaccine
effective for preventing HSV vaginal or skin infections would be effective for preventing HSV ocular disease.
- (c) Koganti describes drug therapies for ocular HSV-1 infections, namely acyclovir and other drugs, aptamers, retrocyclin 2, antibodies, cationic peptides, nucleoside analogs and CRISPR/Cas9. Therefore, combining the cited art does not describe the claimed invention nor provide motivation for a person with ordinary skill in the art to pursue the claimed invention without undue experimentation.
Applicant’s arguments have been considered but are not persuasive. In response to
Applicant’s arguments:
- Regarding item (a), The unexpected results discussed above cover the prevention of an ocular disease both by an active and passive protection mechanism but do not cover the treatment of an HSV ocular disease in a subject infected by HSV-1 as recited by the instant claims. A healthy individual who could be a candidate for a preventive vaccine will have a functional eye’s immune privilege including all the mechanisms contributing to the immune privilege (1). However, when an individual is infected by HSV-1, such infection terminates the eye's immune privilege to fight the virus, leading to immunoinflammatory processes that can cause corneal scarring and blindness. That is, the damage to the cornea is not due to viral replication but to changes in the immune-privileged status of the cornea (including changes to the mechanisms that contribute to the immune privilege - lack of direct lymphatic drainage, a blood-ocular barrier, as well as immunosuppressive and immunoregulatory responses) following HSV-1 infection (Lepisto AJ, Frank GM, Hendricks RL. How herpes simplex virus type 1 rescinds corneal privilege. Chem Immunol Allergy. 2007;92:203-212, Abstract). Additionally, Applicant argues that the antibodies elicited by the vaccine function primarily by activating Fc receptors to mediate the ability of ADCC to protect the immune privileged eye in the case of prevention (1) but no results are discussed of what happens when the eye immune privilege is affected after HSV infection and during HSV ocular disease treatment. Similarly, the passive transfer of immune serum from HSV-2 ΔgD vaccinated mice (2) was less effective against ocular disease compared to vaginal or skin disease in the prevention of ocular compared to vaginal or skin disease but Applicant has not discussed any results regarding such transfer in the case of treatment of an established HSV ocular disease. Passive transfer studies of immune serum from HSV-2 ΔgD vaccinated mice was tested by pooling serum from different mice and bleeds and the pooled serum was tested on naïve mice one day before and four days after corneal inoculation of HSV as a way to study prevention and that the findings suggest that ADCC is protective in the eye and that non-neutralizing antibodies provide greater protection against primary ocular HSV disease than neutralizing antibodies (3). An experiment to investigate if a treatment of an HSV ocular disease is successful would necessarily require the administration of the vaccine after infection has occurred and when the HSV ocular disease is diagnosed, not one day prior to infection when there is no ocular disease yet. An experiment to learn what kind of antibodies would be applicable in an infected subject after treatment of the HSV ocular disease would also require the administration of the vaccine after infection has occurred and when the HSV ocular disease is diagnosed.
In summary, the Applicant has not discussed any unexpected results applicable to treatment of ocular disease caused by HSV-1 in a subject infected with HSV-1 (since HSV-1 establishes latency (lifelong persistent infection of the host) in sensory neurons, once a subject is infected with HSV-1, the subject will be infected for life) as required by the instant claims. Furthermore, a showing of unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements that claimed compound possesses unusually low immune response or unexpected biological activity that is unsupported by comparative data held insufficient to overcome prima facie case of obviousness). MPEP § 2145. Applicant’s statement that the administration of the HSV-2 ΔgD vaccine may prevent HSV-1 ocular disease is not sufficient to demonstrate unexpected results when treating a subject suffering from HSV-1 ocular disease using the HSV-2 ΔgD vaccine as a therapeutic vaccine. There is no indication that the HSV-2 ΔgD vaccine has a dual role in the prevention and treatment of HSV ocular disease and there is no indication that the mechanism of action would be even the same. Most vaccine that are used to prevent a viral infection do not display a dual role of preventing the infection and treating the disease caused by the infection.
It appears as if Applicant is arguing that because the results obtained when preventing an ocular disease by administering the vaccine to a healthy subject may be unexpected, so will the results obtained when the vaccine is administered to a patient suffering from HSV-1 ocular disease be equally unexpected. However, there is no data to support this to be the case so it is a speculative argument and not one based on evidence. A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue.” In re Corkill, 711 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). MPEP 716.02 (a). The evidence relied * > upon < should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). MPEP 716.02 (b). Applicant must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). MPEP 716.02 (b).
- Regarding item (b), Jacobs teachings have been discussed in detail above, including a method of treating a disease caused by HSV-1 in a subject comprising administering the HSV-2 ΔgD virus, and the diseases caused by HSV-1, include HSV keratitis and HSV retinitis. Therefore, it would be obvious to one skilled in the art to use the HSV-2 ΔgD vaccine to treat HSV keratitis and HSV retinitis. Accordingly, Applicant has not sufficiently described why there is no prima facie case for obviousness. Applicant has not demonstrated unexpected results in the case of treatment to overcome the rejection.
- Regarding item (c), The combination of Jacobs and Koganti has been discussed in detail above. Accordingly, Applicant has not sufficiently described why there is no prima facie case for obviousness.
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
Claims 12-15, 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Jacobs (WO 2015/134368 A2 published on September 11, 2015 (US patent 9,999,665 B2)) in view of Betz (US20050053605A1, published on 03/10/2005)
Claims 12-15, 23-24 are drawn to a method of treating ocular disease caused by HSV-1 infection in a first subject by administering to the first subject a product from a second subject to treat the ocular disease in the first subject, wherein the second subject is immunized with HSV-2 ΔgD and is phenotypically complemented with a HSV-1 gD by propagating the HSV-2 in a complementing cell expressing HSV-1 gD, and wherein the product comprises an antibody, an immune factor, or a combination thereof, induced by HSV-1. The ocular disease caused by HSV-1 comprises blepharitis, conjunctivitis, keratitis, retinitis, scleritis, or a combination thereof. The method eliciting an immune response in the first subject against an HSV-1 disease. A product being an antibody (comprising a polyclonal antibody, a monoclonal antibody, or a combination thereof ) or serum elicited by immunization of the second subject with the HSV-2 ΔgD virus propagated in cells expressing HSV-1 gD; the product being a component of a pharmaceutical formulation. The method comprises passive transfer of the product from the second subject to the first subject.
Jacobs teachings have been discussed above. In addition, Jacobs teaches methods for immunizing or eliciting an immune response, passive transfer of the virion or virus or the antibodies or immune factors induced thereby may be effected from one subject to another. The relevant product may be treated after obtention from one subject before administration to a second subject [0099].
Jacobs does not teach the method of treating ocular disease caused by HSV-1 infection in a first subject by the administration of a product (including an anti-HSV1 antibody or an immune factor or serum) from a second subject who has been immunized with HSV-2 ΔgD which has been propagated in a complementing cell expressing HSV-1 gD
Betz teaches that immunoglobulins (antibodies) pooled from human plasma (from HSV infected individuals) can be used to treat another mammal (claims 1-3) and that this mammal suffers from a herpetic disease (claim 4) including herpes ocularis and keratitis (claims 5, 18-20). This method of treatment is known in the art as passive immunity (immunity that develops, is transferred, after a person receives immune system components, most commonly antibodies, from another person).
One of ordinary skill in the art would have been motivated to use the teachings of Jacobs (a vaccine comprising HSV-2 ΔgD to treat ocular HSV-1 infections that can elicit an immune response to be used for passive transfer of antibodies or immune factors) in combination with Betz (treating a first subject who suffers from a herpetic ocular disease with the antibodies obtained from another second subject, who is infected with HSV). That is, passive immunity would be one way to treat a (first) subject for the ocular disease with products obtained from a vaccinated second subject with the goal to improve treatment efficacy. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was 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.
8. Applicant’s arguments are as follows:
- (a) Jacobs does not render the claims obvious since it is not envisaged by a person of ordinary skill in the art from a review of Jacobs that a vaccine effective for preventing HSV vaginal or skin infections would be effective for preventing HSV ocular disease.
- (b) Betz teaches that immunoglobulins pooled from human plasma (from HSV-infected individuals) can be used to treat another mammal and that this mammal suffers from ocularis and keratitis. Betz discusses a method for treating HSV infection by administering intravenously to a mammal an effective amount of a composition comprising immunoglobulin A (IgA) prepared from pooled plasma. Pooled plasma primarily has neutralizing and not ADCC-mediating Abs and as such would not provide the same efficacy as ADCC-mediating antibodies. The claimed invention focuses specifically on passive protection through ADCC (and other Fc mediated antibody functions) as a result of vaccination with HSV-2 ΔgD vaccine. The ability of the HSV-2 ΔgD to provide both active and passive protection against primary lethal HSV-1 corneal disease was a surprising and unexpected result.
Applicant’s arguments have been considered but are not persuasive. In response to
Applicant’s arguments
- Regarding item (a), Jacobs teachings have been discussed in detail above. Applicant has not sufficiently described why there is no prima facie case for obviousness. Applicant has not demonstrated unexpected results in the case of treatment of HSV ocular disease to overcome the rejection as discussed in detail above.
- Regarding item (b), Claims 12-15, 23-24 do not recite any limitation for the type of antibody or the components of the pooled plasma or if these antibodies need to be neutralizing or ADCC-mediating antibodies. Applicant argues that the claimed invention focuses specifically on passive protection through ADCC (and other Fe mediated antibody functions) as a result of vaccination with the HSV-2 ΔgD vaccine and this passive protection is an unexpected result. However, Jacobs teaches that the HSV-2 ΔgD vaccine protected against infection. Also observed was induction of HSV-2 specific CD8+ T cells and systemic and mucosal HSV Abs. IgG2a and IgG2b were the predominant anti-HSV isotype. Also observed was FcyRIII/II-dependent ADCC [00122] (see claim 22 rejection above). Therefore, Jacob teaches the protection through ADCC. In addition, There is no instant claim drawn to passive protection through ADCC (and other Fc mediated antibody functions) as a result of vaccination with HSV-2 ΔgD vaccine. Applicant has not sufficiently described why there is no prima facie case for obviousness for claims 12-15, 23-24. Applicant has not demonstrated unexpected results in the case of treatment to overcome the rejection as discussed in detail above.
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
Claims 22 is rejected under 35 U.S.C. 103 as being unpatentable over Jacobs in view of Betz and Nimmerjahn (PNAS,107 (45) 19396-1940, 2010)
Claim 22 is drawn to a method of preventing or treating ocular disease caused by HSV-1 infection in a first subject by administering to the first subject an antibody specific for an antigen of the HSV-1 to treat the ocular disease in the first subject, wherein the antibody is obtained by immunizing a second subject with HSV-2 ΔgD and being phenotypically complemented with an HSV-1 gD by propagating the HSV-2 in a complementing cell expressing HSV-1 gD, and wherein the antibody elicited by immunizing the second subject with the HSV-2 comprises an Fc receptor-activating antibody.
Jacobs teachings have been discussed above. In addition, Jacobs teaches that HSV-2 ΔgD (propagated in a complementing cell expressing HSV-1 gD) protected against infection. Also observed was induction of HSV-2 specific CD8+ T cells and systemic and mucosal HSV Abs. IgG2a and IgG2b were the predominant anti-HSV isotype. Also observed was FcyRIII/II-dependent Antibody Dependent Cellular Cytotoxicity (ADCC) [00122].
Betz teachings have been discussed above.
Nimmerjahn teaches that IgG2a and IgG2b can bind either to all three (IgG2a binds to FcγRI, III, and IV) or to two (IgG2b binds to FcγRIII and IV) activating FcγRs and that Fcγ receptors are essential for IgG-dependent effector functions including ADCC (page 19396, first column, second paragraph).
One of ordinary skill in the art would have been motivated to use the teachings of Jacobs (a vaccine comprising HSV-2 ΔgD to elicit an immune response that can protect an individual from infection by producing IgG2a and b and by FcyRIII/II-dependent ADCC) in combination with Betz (treating a first subject who suffers from a herpetic ocular disease with the antibodies obtained from another second subject, who is infected with HSV) with Nimmerjahn (IgG2a and IgG2b binding to Fcγ receptors is essential for IgG-dependent effector functions including ADCC) That is, Immunizing a second subject with a vaccine comprising HSV-2 ΔgD to generate IgG2a and b and these IgG2a and b can be used to treat a (first) subject suffering from an ocular disease with the goal to activate the Fc receptor leading to the IgG-dependent effector functions including ADCC. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was 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.
10 Applicant’s arguments are as follows:
- (a) Nimmerjahn looks at the role of individual activating FcγRs for IgGs subclass activity. There is no discussion of ocular HSV-2 nor a description of a method for protecting against ocular infections with HSV-1.
Applicant’s arguments have been considered but are not persuasive. In response to
Applicant’s arguments:
- Regarding item (a), In response to Applicant's arguments against Nimmerjahn, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Claim 22 rejection over Jacobs in view of Betz and Nimmerjahn is discussed in detail above. Applicant has not sufficiently described why there is no prima facie case for obviousness in the case of claim 22 rejection.
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
Double Patenting- Maintained
Claims 1, 3-4, 9 and 11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5 and 6 of U.S. Patent US 10,980,874 B2 ((reference patent) which is a CON of US 10,751,411B2 which is a CON of US 10,391,165, which is a CON of US. 9,999,665) in view of Ligas (J Virol, May 1988, p. 1486-1494) and Xu (Rev Med Virol. 2019; 29: e2054).
Claims 1, 3-4, 9 and 11 have been discussed in detail above and basically they are drawn to a method of treating an HSV-1 ocular disease in a subject comprising administering to the subject the HSV-2 ΔgD virus which is phenotypically complemented with an HSV-1 gD by propagating HSV-2 ΔgD virus in a complementing cell expressing HSV-1 gD.
Claims 5 and 6 of US 10,980,874 B2 are drawn to a method of treating an HSV-1 infection in a subject comprising administering to the subject a genetically engineered HSV-2 comprising an HSV-2 ΔgD virus and an HSV-1 gD on a lipid bilayer thereof. The HSV-1 gD is present on the lipid bilayer of the HSV-2 ΔgD virus-2 by way of infecting a cell with HSV-2 ΔgD virus, wherein the cell is or has been transfected to express the HSV-1 glycoprotein D on a cell membrane, and wherein the HSV-2 ΔgD virus comprising the surface HSV-1 gD on the lipid bilayer is produced from the cell.
Ligas teaches the construction of the cell line able to express HSV -1 gD in an inducible fashion and therefore complement mutant viruses (VD60 cells) (page 1487, “Construction of a cell line able to express HSV -1 gD and complement mutant viruses” Section).The VD60 cell line expresses high levels of HSV-1 gD after being induced by the infection with HSV-2 (figure 1). Mutant viruses lacking gD grown on VD60 cells were able to complete the viral lytic cycle and produce progeny. (That is, the virus is phenotypically complemented by the VD60 cell line) (page 1489, second column first paragraph). In the instant application, the complementing cell in the limitation “by propagating HSV-2 ΔgD virus in a complementing cell expressing HSV-1 gD” is defined as follows: “the virus is grown on complementing cells that express HSV-1 gD (VD60 cells), to yield genotypically gD-null viruses that have incorporated gD-1 on their envelope, allowing for an initial cycle of infection” [4]. In the US 10,980,874 B2 patent, the claims recite the virion as containing the HSV-2 ΔgD virus with an HSV-1 gD on its lipid bilayer envelope “by way of infecting a cell with HSV-2 ΔgD virus, wherein the cell is or has been transfected to express the HSV-1 glycoprotein D on a cell membrane,”. The transfected cell line is defined in Example 1 “Herein a genetically engineered deletion mutant of the gD (U.sub.S6) gene of HSV-2 is disclosed and …... the gD gene was replaced with a DNA fragment encoding the green fluorescent protein (gfp) and Vero cells expressing HSV-1 gD (the VD60 cell line) were transfected with this construct and screened for homologous recombinant virus that formed green plaques” (first paragraph). One of ordinary skill in the art would have been motivated to use the teachings of Ligas (phenotypically complementing an HSV mutant virus lacking gD with a cell expressing HSV-1 gD (VD60 cell line) to produce progeny) in combination with US 10,980,874 B2 (virions containing the HSV-2 ΔgD virus with an HSV-1 gD on its lipid bilayer envelope obtained by propagating the HSV-2 ΔgD virus in a cell expressing the HSV-1 gD (VD60 cell line)) with the instant application (HSV-2 ΔgD virus being phenotypically complemented with an HSV-1 gD by propagating the virus in a cell expressing HSV-1 gD (VD60 cell line)) to generate a product consisting of an HSV-2 ΔgD virus and an HSV-1 gD on a lipid bilayer. It would be obvious that, since the source of the HSV-1 gD needed to phenotypically complement the HSV-2 ΔgD virus (the VD60 cell line) is the same in the instant application as it is in US 10,980,874 B2 patent, the products used in the claimed methods are identical. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was 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.
Xu teaches that both HSV1 and HSV2 are responsible for pandemics of various herpes diseases. These diseases include oral or genital ulcerative lesions, ocular herpes, neonatal herpes or encephalitis (introduction, first paragraph). One of ordinary skill in the art would have been motivated to combine US 10,980,874 B2 (treatment of a herpes disease) with the instant application (treatment of ocular disease) since Xu teaches that ocular herpes diseases is one of the diseases caused by HSV-1 and HSV-2. It is apparent that one of ordinary skill in the art would have had a reasonable expectation of success and therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, especially in the absence of evidence to the contrary.
Claims 1, 3-6, 9 and 11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-7, 12-13, 15, 17, 20-21 of U.S. Patent US 10,076 ,568 B2 (reference patent and DIV of US 9,999,665) in view of Ligas (J Virol, May 1988, p. 1486-1494) and Xu (Rev Med Virol. 2019; 29: e2054)
Claims 1, 3-6, 9 and 11 have been discussed in detail above and basically they are drawn to a method of treating an HSV-1 ocular disease in a subject comprising administering to the subject the HSV-2 ΔgD virus which is phenotypically complemented with an HSV-1 gD by propagating HSV-2 ΔgD virus in a complementing cell expressing HSV-1 gD
Claims 1, 6-7, 12-13, 15, 17, 20-21 of US 10,076 ,568 B2 are drawn to a recombinant HSV-2 virus, a virion (a virus particle) of the recombinant HSV-2, a vaccine of the recombinant HSV-2 virus, wherein the recombinant HSV-2 has a deletion of an HSV-2 gD-encoding gene and comprising an HSV-1 glycoprotein (gD) (HSV-2 ΔgD virus) on a lipid bilayer thereof, and wherein the HSV-1 glycoprotein is not encoded for by the recombinant HSV-2 genome. the HSV-1 gD is present on a lipid bilayer thereof by way of transfecting a cell with a recombinant HSV-2 construct having a deletion of an HSV-2 gD-encoding gene, wherein the cell is or has been transfected to express the HSV-1 gD on a cell membrane, and wherein the recombinant HSV-2 comprising the HSV-1 gD present on a lipid bilayer is produced from the cell (being VD60 cell line) and a pharmaceutical composition comprising the recombinant virus or virion.
Claims 1, 6-7, 12-13, 15, 17, 20-21 of US 10,076 ,568 B2 are not drawn to a method of treating an HSV-1 ocular disease in a subject comprising administering to the subject the recombinant virus, vaccine or virion. However, The specification discloses a method of
treating a disease caused by an HSV-1 using HSV-2 ΔgD virus which is phenotypically complemented with an HSV-1 gD by propagating HSV-2 ΔgD virus in a complementing cell expressing HSV-1 gD (VD60 cell line). The diseases include ocular diseases such as
HSV keratitis and HSV retinitis (specification, column 10 lines 12 to 29).
Ligas teachings have been described in detail above and it would be is obvious that, since the source of the HSV-1 gD needed to phenotypically complement the HSV-2 ΔgD virus (the VD60 cell line) is the same in the instant application as it is in 10,076 ,568 B2 patent, and consequently the products in 10,076 ,568 B2 and the product needed for the treatment method of the instant application are identical.
With regard to obviousness-type double patenting of a method over a patented composition, the Federal Circuit, in Sun v. Lilly, recounts its own decisions in Geneva and Pfizer:
In both cases, we found claims of a later patent invalid for obviousness-type double patenting where an earlier patent claimed a compound, disclosing its utility in the specification, and a later patent claimed a method of using the compound for a use described in the specification of the earlier patent.
Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co., 95 USPQ2d 1797 at 1800 (Fed. Cir. 2010).
In reaffirming its holding in Geneva and Pfizer, the Court finds that a "claim to a method of using a composition is not patentably distinct from an earlier claim to the identical composition in a patent disclosing the identical use.” (Id. at 1801, quoting Pfizer, 518 F.3d at 1363; Geneva, 349 F.3d at 1385-86. The Court reasserts this notion by stating:
[i]t would shock one's sense of justice if an inventor could receive a patent upon a composition of matter, setting out at length in the specification the useful purposes of such composition, . . .and then prevent the public from making any beneficial use of such product by securing patents upon each of the uses to which it may be adapted. Pfizer, 518 F.3d at 1363 n.8 (emphases added); Geneva, 349 F.3d at 1386 (quoting In re Byck, 48 F.2d 665, 666 [9 USPQ 205] (CCPA 1931)).
Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co., 95 USPQ2d 1797 at 1802 (Fed. Cir. 2010).
Therefore, claims 1, 3-6, 9 and 11 of the instant application are found invalid for obviousness-type double patenting since US 10,076 ,568 B2 claimed the same product, disclosing its utility (treating an ocular disease caused by an HSV-1) in the specification.
Claims 12-19 and 21-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 10,391,165 B2 (reference patent and a CON of US 9,999,665 B2) in view of Beztz (US20050053605 A1) and Nimmerjahn (PNAS,107 (45) 19396-1940, 2010).
Claims 12-19 and 21-22 have been discussed above.
Claims 1-4 of US 10,391,165 B2 are drawn to a method of eliciting an immune response in a first subject against an HSV-2 and/or HSV-1 infection by effectuating passive transfer to the first subject of a product (including serum or antibodies) from a second subject immunized with HSV-2 having a deletion of the entire HSV-2 gD-encoding gene and wherein said HSV-2 is phenotypically complemented with an HSV-1 gD by propagating said HSV- 2 in a complementing cell expressing said HSV-1 gD, wherein the subjects may be human.
The claims 1-4 of US 10,391,165 B2 are not drawn to a method of using the product for treatment of an ocular disease and that the product comprises an Fc receptor activating antibody.
Betz teaches that immunoglobulins (antibodies) pooled from human plasma (from HSV infected individuals) can be used to treat another mammal (claims 1-3) and that this mammal suffers from a herpetic disease (claim 4) including herpes ocularis and keratitis (claims 5, 18-20). This method of treatment is known in the art as passive immunity (immunity that develops, is transferred, after a person receives immune system components, most commonly antibodies, from another person).
Nimmerjahn teaches that antibodies such as IgG2a and IgG2b can bind Fcγ receptors which are essential for IgG-dependent effector functions including ADCC (page 19396, first column, second paragraph).
One of ordinary skill in the art would have been motivated to use the teachings of 10,391,165 B2 (eliciting an immune response in a first subject against an HSV-2 and/or HSV-1 infection by effectuating passive transfer to the first subject of an amount of a product from a second subject immunized with HSV-2 ΔgD).) in combination with Betz (treating a first subject who suffers from a herpetic ocular disease with the antibodies (product) obtained from another second subject, who is infected with HSV) with Nimmerjahn ( antibodies such as IgG2a and IgG2b binding to Fcγ receptors and activating their IgG-dependent effector functions including ADCC) That is, Immunizing a second subject with a vaccine comprising HSV-2 ΔgD to generate IgG2a and b and these IgG2a and b can be used to treat a (first) subject suffering from an ocular disease with the goal to activate the Fc receptor leading to the IgG-dependent effector functions including ADCC. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was 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.
Claims 12-19 and 21-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8-11 and 13 of U.S. Patent No. US 10,918,712 B2 (reference patent and a CIP of US 10,391,165 B2 which is a CON of 9,999,665B2) ) in view of Beztz (US20050053605 A1).
Claims 12-19 and 21-22 have been discussed above.
Claims 1-4, 6, 10-11 and 13 of US 10,918,712 B2 are drawn to a method of eliciting an immune response in a first subject against an HSV-2 and/or HSV-1 infection by effectuating passive transfer to the first subject of a product from a second subject immunized with HSV-2 having a deletion of the entire HSV-2 gD-encoding gene and wherein said HSV-2 is phenotypically complemented with an HSV-1 gD by propagating said HSV- 2 in a complementing cell expressing said HSV-1 gD, wherein the product comprises antibodies or immune factors induced thereby, effective to elicit an immune response against an HSV-2 and/or HSV-1 infection in the first subject, wherein the product further comprises an immunological adjuvant.
Claims 8-9 of US 10,918,712 B2 are drawn to a method of inhibiting HSV-1 or HSV-2 viral dissemination (the spread of HSV beyond the initial site of infection) in a first subject comprising administering to a second subject an HSV-2 having a deletion of the entire HSV-2 gD-encoding gene and wherein said HSV-2 is phenotypically complemented with an HSV-1 gD by propagating said HSV- 2 in a complementing cell expressing said HSV-1 gD, effective to preferentially elicit production of Fcγ receptor IV-activating antibodies as compared to neutralizing antibodies in the second subject; and effectuating passive transfer of a product from the second subject to the first subject to inhibit HSV-1 or HSV-2 viral dissemination in the first subject.
Claims 1-4, 6, 8-9, 10-11 and 13 of US 10,918,712 B2 are not drawn to a method of using the product for treatment of an ocular disease.
Betz teaching have been described above.
One of ordinary skill in the art would have been motivated to use the teachings of US 10,918,712 B2 (a vaccine comprising HSV-2 ΔgD to inhibit the spread of HSV-1 beyond the initial site of infection. The vaccine preferentially elicits production of Fcγ receptor IV-activating antibodies. Viral dissemination in the first subject is inhibited by passive transfer of a product from the second subject to the first subject) in combination with Betz (treating a first subject who suffers from a herpetic ocular disease with the antibodies obtained from another second subject, who is infected with HSV). That is, passive immunity would be one way to treat a (first) subject for the ocular disease with products obtained from a vaccinated second subject with the goal to improve treatment efficacy. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was 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.
Applicant has requested that this provisional double patenting rejection be held in abeyance until the claims are otherwise allowable.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671