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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Mar. 19, 2026 has been entered.
Claim Status
Claims 1, 7-16, 19, 25-34, and 37-38 are currently pending in this application.
Claim Objections
Claims 15 and 33 each recites a list of cancers separated by commas, which as opposed to being drafted with standard Markush language, uses nonstandard language which is suggested to be rewritten starting with the article ‘a’ as in “a melanoma” as well with “cancers of unknown primary origin pediatric, solid tumors with unresectable skin lesions” rewritten without any comma if signifying a single cancer as oppose to two different cancer types as in “cancer of unknown primary origin pediatric solid tumor with unresectable skin lesions.” Appropriate correction is required.
Claim Interpretation
In the claims, the preamble of “method for the treatment of cancer” is interpreted as an implied limitation
In the claims, the step of “administering” is interpreted as administering said treatments to a subject, patient or recipient having cancer (e.g., a vertebrate or invertebrate recipient) with the intent of treating cancer (see instant Table 3, Example 2, FIG. 4-5, [0022]).
In the instant claims it is only logical to read the phrases “remaining tumor” and “after a reduction in tumor site” to require the neoadjuvant administering step be performed before the “surgically removing” step at a time after a tumor size has been reduced upon said administering in each of claims 1 and 19. Furthermore, the specification seems to define a “neoadjuvant” treatment as a treatment that precedes a “primary” treatment, i.e., the surgically removing remaining tumor ([0038]-[0039]).
In claims 1 and 19, the terms “neoadjuvant” or “primary” treatment merely represent intended uses/results of performing the claimed method. For purposes of applying art, a purpose or intended use recited in the claims is considered but not given patentable weight when it does not imply any additional limitation to the method step(s) other than those positively recited (MPEP 2111.02). In the instant case, these intended uses recited in the claims do not imply anything additional to the claims because, in view of the specification, a “neoadjuvant” treatment is a treatment before a “primary” treatment and a surgery is a “primary” treatment ([0038]-[0039]; [0083]), which is performed subsequently in the claimed method. Furthermore, a neoadjuvant effect(s) in a recipient subject is considered an inherent result of performing the method as positively recited regardless of intentions.
Similarly for claim 19, the “adjuvant” treatment is an intended use/result of performing the claimed method. For purposes of applying art, a purpose or intended use recited in the claims is considered but not given patentable weight when it does not imply any additional limitation to the method step(s) other than those positively recited (MPEP 2111.02). In the instant case, this intended use does not imply anything additional to the claims because, in view of the specification, there is not always a distinction between a “primary” treatment and an “adjuvant” treatment beyond timing as both a “primary” and “adjuvant” treatment includes an identical checkpoint inhibitor therapy ([0083]-[0084]). Similarly, as used in the instant application, there is not always a distinction between an “adjuvant” treatment and an “neoadjuvant” treatment except the possibility of timing, as both a neoadjuvant and adjuvant treatment may consist of a checkpoint inhibitor therapy, BRAF inhibitor therapy, and MEK inhibitor therapy ([0084]; [0038]). Furthermore, an adjuvant effect(s) in a recipient subject (e.g., immune stimulation or suppression of secondary tumor formation) is considered an inherent result of performing the method as positively recited regardless of intentions. Thus, the adjuvant treatment step of claim 19 may be performed before, during or after the neoadjuvant treatment and before, during or after the primary treatment regardless of the order of steps recited.
In claim 16, the cancer of claim 1 is limited to a melanoma of a particular cancer stage; however as noted above, the method of claim 1 allows for an indefinite passage of time between the neoadjuvant treatment (neoadjuvant administering step) and the primary treatment (surgically removing step). Thus, the melanoma stage of claim 16 is interpreted as being at any time during the entire treatment of cancer method, e.g., including wherein Stage 2 had not yet been reached during the neoadjuvant administering step but is subsequently reached before or during the primary treatment.
In claim 34, the cancer of claim 19 is limited to a melanoma of a particular stage; however as noted above, the method allows for any passage of time between the neoadjuvant administering step and the surgically removing step as well as for the timing of the adjuvant treatment, thus the melanoma stage is interpreted as being at any time during the treatment method, e.g., including wherein Stage 2 had not yet been reached during the neoadjuvant administering step or surgically removing step but is subsequently reached before or during a subsequent adjuvant treatment (checkpoint inhibitor administering step) so long as this is considered part of the overall method for treatment of cancer.
Response to Remarks
Applicant’s remarks of Mar. 19, 2026 (pg. 7-8) are fully considered but not found to be persuasive. Applicant argues that the claimed method requires the neoadjuvant treatment results in the reducing of the size of the tumor as an effect. This is contrary to the interpretation above, which under a broadest reasonable interpretation instead reads the claims as drafted to only require a method for the treatment of cancer merely comprising a reduction in tumor size, with no requisite cause or mechanism. First, it is noted both claims 1 and 19 are written with the open-ended transition “comprising” and, thus, the reduction in tumor size is only strictly implied as being an effect/result of the administration of the neoadjuvant treatment when no other additional administering or anti-cancer intervention not involving tumor removal surgery is taken before administering the treatment comprising surgical removing of remaining tumor. If applicant desires the reduction in tumor size to necessarily be a result of an oncolytic virus and/or checkpoint inhibitor administrating step, then the claim language needs amending to expressly add such a limitation(s) as no such limitation is strictly implied as interpreted herein.
Regarding claim 19, applicant argues that the adjuvant treatment step must occur after both the neoadjuvant and primary treatment steps (i.e., in the order of the steps as written). This is contrary to the broadest reasonable interpretation above which lacks any specific timing for the adjuvant treatment step. As noted previously in the record, a neoadjuvant treatment as defined by the instant application occurs before a primary treatment while an adjuvant treatment has no defined timing. Further, the specification makes no clear distinction between a neoadjuvant and adjuvant treatment when both can consist merely of administering to a subject a checkpoint inhibitor, BRAF inhibitor therapy or MEK inhibitor therapy (instant [0084], [0038]) nor any distinction between a primary and adjuvant treatment when both can consist merely of a checkpoint inhibitor, BRAF inhibitor therapy, MEK inhibitor therapy, and/or combinations thereof ([0038], [0083]-[0084]). Thus, the adjuvant treatment administration of claim 19 may optionally be either after the primary treatment or before the primary treatment (perhaps acting indistinguishably from the so-called “neoadjuvant” treatment) as well as during either the neoadjuvant and/or primary treatment, e.g., wherein an immune checkpoint inhibitor is administered throughout the entire method for treatment of cancer.
The MPEP (2111.01(II)) notes it is generally improper to read a specific order of steps into method claims unless, as a matter of logic or grammar, there is an implicitly required order that one step must precede a second step. The broadest reasonable interpretation of claim 19 has no implied order by either logic or grammar for the administering the adjuvant treatment as interpreted herein; however, it would be remedial to expressly set the desired order of any of the method steps by amending claim 19, and/or if desired to distinguish an adjuvant treatment from a neoadjuvant treatment.
Claim Rejections - 35 USC § 112(a), Written Description
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, 7-16, 19, 25-34, and 37-38 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 for failing to particularly point out and distinctly claim the subject matter. The claim(s) contains 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.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicant’s effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of. The invention of claim 1 or 19 is a method comprising (1) administering a neoadjuvant treatment comprising a modified HSV-1 oncolytic virus, (2) surgically removing any remaining tumor after a reduction in tumor size (e.g., due to the neoadjuvant treatment), and (3) administering a checkpoint inhibitor (either as part of the neoadjuvant treatment or as a separate adjuvant treatment, respectively).
The preamble of “for the treatment of cancer” is a recited intended purpose/use that limits the claimed methods to be capable of treating a cancer with reasonable predictability despite no implication of any unrecited structure beyond an organism with cancer in need of the treatment.
The instant specification only describes working examples wherein the method is applied to a human with stage 3 or 4 melanoma and at least one lesion equal or larger than 10 mm (Examples 1-2).
Administering
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that are not conventional in the art as of applicants effective filing date, such as structures/functions to define the recipient of the administering. While the claims imply the administering is to an organism having cancer, such as a human, nowhere do the claims make this clear. Thus, the administering steps (i.e., of a particular treatment) could encompass administering to anything or anyone, including a patient or ex vivo cells or tissues thereof in furtherance of a cancer treatment. Furthermore, of subjects having cancer, this is a wide genus encompassing both vertebrates and invertebrates (see Albuquerque et al., Biol. Rev. 93: 1715-34 (2018) at pg. 1729, e.g., in mollusks).
The instant specification only describes working examples wherein treatment administration is to a human subject by undescribed means and dosing known in the art (e.g., standard for talimogene laherparepvec at the time) (Examples 1-2). Therefore, the skilled artisan cannot envision the full scope of claim 1 wherein the administering is to ex vivo cells or tissues of a patient or wherein the subject is not a vertebrate. The instant application is silent as to any invertebrate subject as well as any vertebrate subject that is not a mammal (e.g., human, bovine, equine, canine, ovine, or feline) (see [0022]). None of the dependent claims correct this deficiency.
Heterologous Protein
The genus of heterologous protein is interpreted as encompassing any protein unlimited by structure and function (see 112(b) rejection below). This represents an enormously vast genus encompassing all known proteins, e.g., the Swiss-Prot database contains over 500,000 proteins (see UniProtKB/Swiss-Prot - SIB Swiss Institute of Bioinformatics or UniProt). The protein structure is also unlimited by size, and thus the claimed invention encompasses genes encoding very large proteins, such as titin or PKZILLA-1, which has an ORF (coding sequence) of over 130,000 base pairs (Fallon et al., Science 385: 671-8 (2024)). However the prior art teaches no HSV-1 virus that can package a nucleic acid that large and the instant specification is silent as to any increase in HSV-1 packaging sizes over the prior art. Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the enormously vast genus of genes encoding any protein that can incorporated into the genome of an oncolytic HSV-1 virus, such as wherein the gene is unlimited in size. Claims 7-8 and 25-26 overcome this breadth by narrowing the protein to a cytokine.
Furthermore, there is no evidence of functional difference to the claimed method that a modified HSV-1 merely encoding a heterologous protein. Thus, this claim limitation appears superfluous to the methods of claims 1, 9-16, 19, 27-34, and 37-38. Regarding claims 7 and 25, even if expression in the recipient or host cell thereof is required, the narrowing of the protein to a cytokine is still a broad genus as all vertebrate species have multiple cytokines and some invertebrates have IL-1, IL-2, IL-4, IL-6, IL0, and IL-17 cytokine homologs (Gerber et al., Invertebrate Survival Journal 4: 95-100 (2007) at pg. 97).
Any Cancer
The scope of the term “cancer” in the preamble of claim 1 or 19 encompasses any cancer. Nowhere do the claims or application formal define or redefine the term cancer. The instant application only mentions a limited set of types of cancers ([0009], [0042], [0047], [0052]) with working embodiments only for later stage melanoma in humans. There is no established nexus in the prior art between melanoma and oncolytic viral therapy with treating all other cancers and none is provided in the instant disclosure. Therefore, the skilled artisan cannot envision the full scope of claim 1 or 19 wherein the method is for treating a cancer other than melanoma. While claims 15 and 33 recited a narrower cancer genus, this does not cure this deficiency.
Therefore, 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 inventors, at the time the application was filed, had possession of the full scope of the invention as claimed.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 7-16, 19, 25-34, and 37-38 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claims 1 and 19 each recite the phrases “a reduction in tumor size” and “remaining tumor,” however said “tumor” lacks sufficient antecedent in the claim, for example, because a subject having cancer may not have any tumor (e.g., a leukemic cancer). Claims 7-16, 25-34, and 37-38 are included in this rejection for depending from indefinite claim 1 or 19.
Claims 1 and 19 each recites the term “heterologous protein”; however, it is ambiguous, incoherent and unclear as what the protein is heterologous regarding, either the recipient of the administering and/or the HSV-1 oncolytic virus comprising it. As “heterologous” is a relative term, the term as used is indefinite for not being anchored to any reference (e.g., a species, virus type, or subject) because neither the claim nor the specification provides a standard or means for determining a boundary for a “heterologous” protein to inform the skilled artisan of the metes and bounds of this limitation. All proteins are considered heterologous to something else, if that something else is unlimited. Claims 7-16, 25-34, and 37-38 are included in this rejection for depending from indefinite claim 1 or 19.
In claims 15 and 33, recites said cancer is “or cancers of unknown primary origin, pediatric solid tumors with unresectable skin lesions,” which is incoherent, ambiguous and unclear as to use of the plural terms “cancers” and “tumors” as well as the grammatical position off the term ‘or.’ Claims 16 and 34 are included in this rejection for depending from indefinite claim 15 or 33.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-3 and 20-21 are rejected 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.
In claims 2-3 and 20-21, even when the oncolytic virus is limited to a herpes simplex virus, these claims are broadening from the narrower subclass of herpes simplex viruses encompassed by an HSV-1 (herpes simplex 1 viruses). A dependent claim of claim 1 or 19 cannot expand the scope of the oncolytic virus already limited to a modified HSV-1 to any herpes simplex virus.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 7-11, 13, 15-16 and 37 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Gansert (WO2018201028A1, priority to 2018-04-27; IDS ref.).
Regarding claim 1, Gansert discloses a method of treating cancer by administering a combination therapy comprising an oncolytic virus and an immune checkpoint inhibitor (pembrolizumab) (Abstract; [059]-[062]) prior to surgery to remove an entire remaining tumor ([0163]), wherein the virus is a modified HSV-1 (talimogene laherparepvec) comprising a transgene encoding a heterologous protein (human GM-CSF) and lacking any functional ICP34.5 and ICP47 genes ([0103]-[0104]; [0108]). Gansert aims to reduce tumor size, reduce the number of cancer cells, and reduce the rate of tumor growth via the cancer treatment comprising talimogene laherparepvec administering ([0147]). Thus, although Gansert does not expressly explain the surgical resection following the modified HSV-1 administering is for removing a reduced in size remaining tumor, this is an expected inherent occurrence in view of the mechanistic statements of Gansert ([0147]) when there is any gap in time between the talimogene laherparepvec administering and the subsequent surgery to remove tumor ([0162]).
Regarding claims 7-9 and 37, Gansert discloses wherein the oncolytic virus is talimogene laherparepvec, which is a type of herpes simplex virus engineered to express the heterologous cytokine GM-CSF (id.).
Regarding claims 10-11 and 13, Gansert discloses the immune checkpoint inhibitor the PD-1 blocker anti-PD-1 antibody pembrolizumab (Abstract; [0115]).
Regarding claims 15-16, Gansert discloses wherein the cancer is melanoma, breast cancer, renal cancer bladder cancer, colorectal cancer, lung cancer, pancreatic, or head and neck cancer ([012], [021], [025], [033], [036]), such as melanoma Stage 3b, 3c, or 41a (e.g., IIIB to IVM1c) (Examples 1 and 8).
Thus, Gansert anticipates the claimed invention.
Claims 1, 7-16, 19, 25-34, and 37-38 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Conner (WO2017013419A1).
Regarding claims 1 and 37, Conner discloses a method of treating cancer by administering a checkpoint inhibitor and the oncolytic virus (Abstract; pg. 13, line 15, to pg. 14, line 4; pg. 31, lines 21-23) that is a modified herpes simplex HSV-1 virus lacking functional ICP34.5 and ICP47 genes and comprising a gene encoding a heterologous protein (hGM-CSF), i.e., talimogene laherparepvec, strain JS1 or OncoVEX GM-CSF (ICP34.5-/ICP47-/hGM-CSF)) (pg. 41, line 33, to pg. 42, line 24, pg. 25, ¶ 7; pg. 45, lines 8-14) and wherein, after completing viral administration, a tumor surgical resection is performed, or a treatment cycle thereof, in order to remove a tumor (pg. 40, lines 9-18). Although Conner does not expressly disclose an aim of post-viral/inhibitor therapy surgery is for removing “any remaining tumor,” it is understood that in performing certain surgeries involving solid tumor resection, a surgeon would attempt to remove as much tumor tissue as considered possible by a medical practitioner even when the primary goal is to obtain a solid tumor biopsy as indicated by Conner at pg. 40, lines 14-19; pg. 31, lines 27-29. Furthermore, although Conner does not disclose the tumor size is reduced by the oncolytic virus administration prior to the surgical resection step potentially removing all remaining tumor (pg. 40, pg. 31, lines 27-29), Connor teaches oncolytic virotherapies are expected to induce tumor shrinkage via a multistep process including direct tumor cell lysis, induction of cytotoxic or apoptosis-sensitizing cytokines, and induction of antitumor T cell responses (Example 3). Thus, the modified HSV-1 administering in a method of Connor is for reducing the size of tumors as an expected inherent occurrence when there is any gap in time between the modified HSV-1 administering and the subsequent surgery to remove tumor, which is disclosed as occurring within 14 days of the last dose of modified HSV-1 therapy (pg. 31, lines 27-29).
Regarding claims 7-9, Conner discloses the oncolytic talimogene laherparepvec virus is a type of herpes simplex virus engineered to express the heterologous cytokine human GM-CSF (pg. 45, lines 8-14).
Regarding claims 10-14, Conner discloses wherein the immune checkpoint inhibitor is a CTLA-4 blocker, PD-1 blocker, or PD-L1 blocker, including specifically the anti-CTLA-4 antibody ipilimumab, the anti-PD-1 antibody nivolumab, pembrolizumab, CT-011, or AMP-224, and the anti-PD-L1 antibody BMS-936559 (pg. 47, line 27, to pg. 49, line 4).
Regarding claim 15, Conner discloses wherein the cancer to be treated is a melanoma, T cell lymphoma, breast cancer, lung cancer, colorectal cancer, or pancreatic cancer (pg. 53, lines 16-27).
Regarding claim 16, Conner discloses the melanoma may be Stage 3b, 3c, 3d, or 4 melanoma (e.g., IIIB to IV) (pg. 10, line 29; pg. 21, lines 1-2; pg. 56, line 9).
Regarding claims 19 and 38, Conner discloses a method of treating cancer by (1) administering the HSV-1 oncolytic virus talimogene laherparepvec, (2) administering an immune checkpoint inhibitor, and then later performing a tumor surgical resection after completing a viral treatment in order to resect a tumor (pg. 13, line 15, to pg. 14, line 34; pg. 17, line 14, to pg. 18, line 2; pg. 18, lines 25-35; pg. 4, lines 5-7, 13-15, 19-29; pg. 9, lines 25-27; pg. 31, lines 21-23; pg. 40, lines 9-18) wherein talimogene laherparepvec lacks functional ICP34.5 and ICP47 genes but comprises a gene encoding the heterologous protein cytokine hGM-CSF (pg. 41, line 33, to pg. 42, line 24, pg. 25, ¶ 7; pg. 45, lines 8-14) and wherein a tumor surgical resection is performed after completing viral administration, or a treatment cycle thereof, in order to remove a tumor (pg. 40, lines 9-18). Although Conner does not expressly disclose an aim of post-viral/inhibitor therapy surgery is for removing “any remaining tumor,” it is understood that in performing certain surgeries involving solid tumor resection, a surgeon would attempt to remove as much tumor tissue as considered possible by a medical practitioner as indicated by Conner at pg. 40, lines 14-19; pg. 31, lines 27-29.
Regarding claims 25-27, Conner discloses the oncolytic talimogene laherparepvec virus is a type of herpes simplex virus engineered to express the heterologous cytokine human GM-CSF (pg. 45, lines 8-14).
Regarding claims 28-32, Conner discloses wherein the immune checkpoint inhibitor is a CTLA-4 blocker, PD-1 blocker, or PD-L1 blocker, including specifically the anti-CTLA-4 antibody ipilimumab, the anti-PD-1 antibody nivolumab, pembrolizumab, CT-011, or AMP-224, and the anti-PD-L1 antibody BMS-936559 (pg. 47, line 27, to pg. 49, line 4).
Regarding claim 33, Conner discloses wherein the cancer to be treated is a melanoma, T cell lymphoma, breast cancer, lung cancer, colorectal cancer, or pancreatic cancer (pg. 53, lines 16-27).
Regarding claim 34, Conner discloses the melanoma may be Stage 3b, 3c, 3d, or 4 melanoma (e.g., IIIB to IV) (pg. 10, line 29; pg. 21, lines 1-2; pg. 56, line 9).
Thus, Conner anticipates the claimed invention.
Response to Arguments
Applicant’s arguments of Mar. 19, 2026 (pg. 10-13) are fully considered but not found to be persuasive.
Applicant traverses the previous 102 rejections by arguing Conner does not describe the intent of tumor surgery as a “primary” treatment but rather for the purpose of obtaining a tumor sample. Applicant argues that the claims as amended distinguish over Conner by requiring a reduction in tumor size prior to surgical resection of remaining tumor as a “primary” treatment as purportedly Conner is silent as to any “primary” treatment after tumor size is reduced.
However as noted above, the meaning/definition of “primary” treatment is interpreted as limiting only relating to timing but otherwise represents an intended purpose with no implied limitation for the purposes of applying prior art, and as both Gansert and Conner each teaches an oncolytic virus treatment followed by tumor removal surgery treatment, the prior art teaches the method claims as positively recited whenever the tumor size has been reduced (e.g., by a minimal amount) prior to the surgical resection.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 7-16, 19, 25-34, and 37-38 are rejected under 35 U.S.C. 103 as being unpatentable over Conner (WO2017013419A1) in view of Andtbacka (Andtbacka et al., Journal of Clinical Oncology 36(15 Suppl): 9508 (2018); IDS ref.).
The claims are interpreted as explained in a previous section.
Conner teaches methods of treating cancer by administering an oncolytic virus an and an immune checkpoint inhibitor, either simultaneously or the inhibitor subsequent to the virus, wherein the virus is a modified Herpes simplex virus HSV-1 strain lacking functional ICP34.5 and ICP47 genes (e.g., talimogene laherparepvec, strain JS1 or OncoVEX GM-CSF (ICP34.5-/ICP47-/hGM-CSF)) and comprising a gene encoding a heterologous protein (hGM-CSF), such as wherein a tumor surgical resection is performed after completing the administering in order to remove remaining tumor (Abstract; pg. 13, line 15, to pg. 14, line 4; pg. 31, lines 21-23; pg. 41, line 33, to pg. 42, line 24, pg. 25, ¶ 7; pg. 45, lines 8-14; pg. 40, lines 9-18; pg. 14, lines 24-34; pg. 17, line 14, to pg. 18, line 2; pg. 18, lines 25-35; pg. 4, lines 5-7, 13-15, 19-29; pg. 7, lines 14-15; pg. 9, lines 25-27; pg. 31, lines 21-23).
Regarding claim 1, Conner does not expressly teach the goal of administering the virus and checkpoint inhibitor is to assist or improve a subsequent surgical treatment for the cancer.
However Andtbacka teaches administering talimogene laherparepvec (T-VEC) to cancer patients as neoadjuvant treatment prior to surgery and reports improvements in pathological responses and therapeutic outcomes (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the time of filing to apply a method of Conner using talimogene laherparepvec and an immune checkpoint inhibitor as a neoadjuvant therapy to assist the effectiveness of a subsequent surgery to remove a tumor(s). One of ordinary skill in the art would be motivated by Andtbacka to combine a virotherapy for cancer using talimogene laherparepvec with surgical therapies for cancer whereby the virotherapy is intended to reduce tumor volume or otherwise assist or improve surgical outcomes, i.e., has a neoadjuvant effect. Although Conner does not clearly teach the aim of post-viral/inhibitor therapy surgery is for removing “any remaining tumor,” it is understood that in performing therapeutic surgery involving solid tumor resection, a surgeon would attempt to remove as much tumor tissue as possible, i.e., any remaining tumor.
Regarding claims 7-9 and 37, Conner teaches wherein the oncolytic virus is a modified HSV-1 that lacks functional ICP34.5 and ICP47 genes (pg. 3, lines 27-31; pg. 5 lines 14-16; pg. 10, lines 1-8; pg. 19, lines 26-33; pg. 41, line 33, to pg.42, line 13), such as Talimogene laherparepvec (pg. 45 lines 8-14), and comprises a gene encoding a heterologous cytokine gene (pg. 43, line 30, to pg. 44, line 8; pg. 44, lines 18-25), such as the cytokine GM-CSF (pg. 3, lines 27-31; pg. 45, lines 1-2; pg. 13 lines 1-7; pg. 24, lines 1-7), such as wherein both ICP34.5 and ICP47 functionally deleted and the heterologous coding sequence for human GM-CSF is inserted into the viral genome such that it replaces nearly all of the ICP34.5 gene (pg. 45, lines 8-14).
Regarding claims 10-14, Conner teaches wherein the immune checkpoint inhibitor is a CTLA-4 blocker, PD-1 blocker, or PD-L1 blocker, including specifically the anti-CTLA-4 antibody ipilimumab, the anti-PD-1 antibody nivolumab, pembrolizumab, CT-011, or AMP-224, and the anti-PD-L1 antibody BMS-936559 (pg. 47, line 27, to pg. 49, line 4).
Regarding claim 15, Conner teaches wherein the cancer treated is a melanoma (pg. 53, lines 16-27), and Andtbacka teaches wherein the cancer treated is melanoma (Abstract).
Regarding claim 16, Andtbacka teaches wherein the melanoma is Stage 3b, 3c, 3d, or 4 melanoma (e.g., IIIB to IVM1a), and Conner teaches the melanoma may be Stage 3b, 3c, 3d, or 4 melanoma (e.g., IIIB to IV) (pg. 10, line 29; pg. 21, lines 1-2; pg. 56, line 9).
Regarding claim 19, Conner teaches a method of treating cancer by (1) administering an oncolytic virus (Herpes simplex virus (HSV-1) talimogene laherparepvec), (2) administering an immune checkpoint inhibitor (Abstract), and (3) performing a tumor surgical resection after completing a viral treatment in order to remove all the tumor tissue (pg. 13, line 15, to pg. 14, line 34; pg. 17, line 14, to pg. 18, line 2; pg. 18, lines 25-35 pg. 4, lines 5-7, 13-15, 19-29; pg. 9, lines 25-27; pg. 31, lines 21-29; pg. 40, lines 9-18; pg. 7, lines 14-15). However Conner does not expressly teach the goal of administering the virus is to assist or improve a subsequent surgical treatment for the cancer, Conner anticipates the effect of reducing the size of tumors in a subject via HSV-1 administration (Example 3). Thus, the modified HSV-1 administering in a method of Connor is for reducing the size of tumors as an expected inherent occurrence when there is any gap in time between the modified HSV-1 administering and the subsequent surgery to remove tumor, which is disclosed as occurring within 14 days of the last dose of modified HSV-1 therapy (pg. 31, lines 27-29). Furthermore, it is understood that in performing certain surgeries involving solid tumor resection, a surgeon would attempt to remove as much tumor tissue as considered possible by a medical practitioner as indicated by Conner at pg. 40, lines 14-19; pg. 31, lines 27-29.
It would have been prima facie obvious to one of ordinary skill in the art before the time of filing to apply the method of Conner using talimogene laherparepvec as a neoadjuvant therapy to assist the effectiveness of a subsequent surgery to remove a tumor(s) wherein administering an immune checkpoint inhibitor is performed before or after surgery. One of ordinary skill in the art would be motivated by Andtbacka to combine a virotherapy for cancer using talimogene laherparepvec with surgical therapies for cancer whereby the virotherapy is intended to reduce tumor volume or otherwise assist or improve surgical outcomes, i.e., has a neoadjuvant effect. Furthermore, it would have been prima facie obvious to have the surgical goal of removing any remaining tumor as it is understood that in performing therapeutic surgery involving solid tumor resection, a surgeon would attempt to remove as much tumor tissue as possible.
Regarding claims 25-27 and 38, Conner teaches wherein the oncolytic virus is a modified HSV-1 that lacks functional ICP34.5 and ICP47 genes (pg. 3, lines 27-31; pg. 5 lines 14-16; pg. 10, lines 1-8; pg. 19, lines 26-33; pg. 41, line 33, to pg.42, line 13), such as Talimogene laherparepvec (pg. 45, lines 8-14), and comprises a gene encoding a heterologous cytokine gene (pg. 43, line 30, to pg. 44, line 8; pg. 44, lines 18-25), such as the cytokine GM-CSF (pg. 3, lines 27-31; pg. 45, lines 1-2; pg. 13 lines 1-7; pg. 24, lines 1-7).
Regarding claims 28-32, Conner teaches wherein the immune checkpoint inhibitor is a CTLA-4 blocker, PD-1 blocker, or PD-L1 blocker, including specifically the anti-CTLA-4 antibody ipilimumab, the anti-PD-1 antibody nivolumab, pembrolizumab, CT-011, or AMP-224, and the anti-PD-L1 antibody BMS-936559 (pg. 47, line 27, to pg. 49, line 4).
Regarding claim 33, Conner teaches wherein the cancer treated is a melanoma (pg. 53, lines 16-27), and Andtbacka teaches wherein the cancer treated is melanoma (Abstract).
Regarding claim 34, Andtbacka teaches wherein the melanoma is Stage 3b, 3c, 3d, or 4 melanoma (e.g., IIIB to IVM1a), and Conner teaches the melanoma may be Stage 3b, 3c, 3d, or 4 melanoma (e.g., IIIB to IV) (pg. 10, line 29; pg. 21, lines 1-2; pg. 56, line 9). Thus, the claimed invention as a whole is prima facie obvious to one of ordinary skill in the art before the earliest effective time of filing in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments of Mar. 19, 2026 are fully considered but not found to be persuasive.
Applicant traverses the previous 103 rejections by arguing Conner does not describe surgery as a primary treatment but rather for the purpose of obtaining a tumor sample, and for this reason, Conner cannot disclose the use of an oncolytic virus and immune checkpoint inhibitor in combination with surgical treatment.
Conclusion
No claim is allowed.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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