Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed January 16, 2026.
Amendments
Applicant's response and amendments, filed January 16, 2026, is acknowledged. Applicant has cancelled Claims 1-13, 15, and 19-21, amended Claim 14, and added new claims, Claim 22.
Claims 14, 16-18, and 22 are pending and under examination.
Priority
This application is a 371 of PCT/EP2020/082888 filed November 20, 2020.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).
Certified copies of:
EPO 20193706.7 filed August 31, 2020;
EPO 20191226.8 filed August 14, 2020; and
EPO 19210369.5 filed November 20, 2019,
are provided with the instant application.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on January 16, 2026 that has been considered.
The information disclosure statement filed January 16, 2026 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
Bibliographic information provided must be at least enough to identify the publication. author, title and date. For books, minimal information includes the author, title, and date. For periodicals, at least the title of the periodical, the volume number, date, and pages should be given.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Allowable Subject Matter
1. Claim 22 would be allowable if rewritten or amended to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, set forth in this Office action.
The following is a statement of reasons for the indication of allowable subject matter:
Claim 22 recites a FOLR1-PRAME fusion protein whose amino acid sequence consists of SEQ ID NO:9 (741 amino acids), which appears to be free of the prior art.
Claim Objections
2. The prior objection to Claim 14 is withdrawn in light of Applicant’s amendment to the claim.
Claim Rejections - 35 USC § 112
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.
3. The prior rejection of Claims 14-21 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s cancellation of “locally” and instead recite “intratumorally”, which the Examiner finds persuasive.
4. The prior rejections of Claims 15 and 19-21 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, are withdrawn in light of Applicant’s cancellation of the claims.
5. Claim 22 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 22 recites the phrases “the sequence set forth in SEQ ID NO”.
As a first matter, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 22 recites the broad recitation “the sequence set forth in”, and the claim also recites “SEQ ID NO”, which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language, SEQ ID NO:9, is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
As a second matter, the phrase “the sequence set forth in SEQ ID NO…”, which renders the claim indefinite because the referenced SEQ ID NO is composed of a plurality of amino acid subsequences, respectively.
The Directors Technology Center 1600 Memorandum, Nucleic Acid and Peptide Claim Interpretation: “A” and “The” (December 29, 2005) informs the TC1600 Examiners that the phrase “A nucleic acid comprising a nucleotide sequence of SEQ ID NO:1” encompasses nucleic acids that comprise any portion of SEQ ID NO:1; whereas, the phrase “A nucleic acid comprising the nucleotide sequence of SEQ ID NO:1” is directed only to nucleic acids that comprise the full length of SEQ ID NO:1.
English has two articles: ‘the’, and ‘a/an’.
‘the’ is a definite article, referring to a specific or particular noun; whereas, ‘a/an’ is an indefinite article, modifying non-specific or non-particular nouns.
The claim(s) are considered indefinite because it is unclear which amino acid sequence within SEQ ID NO:9 is required to be present, and which amino acid sequence within SEQ ID NO:9 may be absent.
As a four matter, the claims recite the phrases “set forth in” which renders the claims indefinite because the reference SEQ ID NO’s are each composed of a plurality of amino acid subsequences, respectively, and it is unclear to which subsequence “set forth in” the reference SEQ ID NO Applicant refers.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
The Examiner suggests amending the claims cancelling recitation of “set forth in”, and instead recite “the sequence of SEQ ID NO”.
Claim Rejections - 35 USC § 102
6. The prior rejection of Claim(s) 14 and 16 under pre-AIA 35 U.S.C. 102(b)(1) as being anticipated by Kupper et al (U.S. 2014/0186298) is withdrawn in light of Applicant’s amendment to the independent claim to recite intratumoral administration of the rMVA to the subject, a limitation Kupper et al do not disclose.
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
7. Claims 14 and 16 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Kupper et al (U.S. 2014/0186298; of record) in view of Kudo-Saito et al (Intratumoral Vaccination and Diversified Subcutaneous/ Intratumoral Vaccination with Recombinant Poxviruses Encoding a Tumor Antigen and Multiple Costimulatory Molecules, Clin. Cancer Res. 10: 1090-1099, 2004; hereafter Kudo-Saito-1), Martinet et al (T cell activation with systemic agonistic antibody versus local 4-1BB ligand gene delivery combined with interleukin-12 eradicate liver metastases of breast cancer, Gene Therapy 9: 786-792, 2002), and Kudo-Saito et al (4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines, Vaccine 24: 4975-4986, 2006; hereafter Kudo-Saito-2; of record in IDS).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 14, Kupper et al is considered relevant prior art for having disclosed a method of stimulating an immune response in a cancer subject (e.g. claims 4 and 7), the method comprising the step of topically administering the rMVA to the subject (e.g. [0020], MVA immunization via skin scarification elicits dose-dependent immune response; claim 5).
Kupper et al also disclosed wherein the rMVA is administered to the subject subcutaneously (e.g. Example 1; [0010, 247]).
Kupper et al disclosed the recombinant viral vector encodes multiple immunogenic fragments and/or at least two to ten different genes [0066], whereby the one or more tumor-associated antigens may be combined with an immunomodulatory protein (e.g. [0065]), wherein the immunomodulatory protein includes 4-1BBL (e.g. [0163]; claim 13).
Kupper et al do not disclose administering intratumorally to the subject the rMVA.
However, prior to the effective filing date of the instantly claimed invention, Kudo-Saito-1 is considered relevant prior art for having taught a method of stimulating an immune response in a subject, the method comprising the step of administering via intratumoral injection in said subject a recombinant vaccinia vector cancer vaccine encoding a tumor-associated antigen and at least one immunostimulatory molecule (e.g. Title, Abstract). Kudo-Saito-1 taught that the combination of a subcutaneous administration prime and an intratumoral administration boost induced an antitumor response therapy superior to either route individually (e.g. Abstract).
Martinet et al is considered relevant prior art for having taught intratumoral injection of a viral vector expressing 4-1BBL (e.g. Abstract), whereby 4-1BBL was previously recognized in the art to amplify T cell-mediated immunity (e.g. pg 786, col. 2).
Kudo-Saito-2 is considered relevant prior art for having taught a recombinant vaccinia virus expressing 4-1BBL in combination with a recombinant vaccinia virus expressing a tumor antigen, to wit, CEA, whereby the 4-1BBL-expressing virus significantly enhanced the therapeutic effects against CEA-expressing tumors (e.g. Abstract), whereby the combination of the 4-1BBL-expressing virus and the CEA-expressing virus yielded a synergistically greater therapeutic response than the 4-1BBL-expressing virus or the CEA-expressing virus alone (e.g. Figure 2).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, immunology, and the design of viral expression vectors. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a subcutaneous administration of an rMVA vaccine vector, as disclosed by Kupper et al, with intratumoral administration, in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute subcutaneous administration with intratumoral administration in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector because those of ordinary skill in the art had long-recognized the scientific and technical concepts that the subcutaneous administration route may be substituted with intratumoral administration route, as successfully demonstrated by Kudo-Saito-1 and Martinet et al, whereupon Kudo-Saito-1 taught that the intratumoral vaccination was superior in inducing antitumor effects as compared to conventional subcutaneous vaccination (e.g. pg 1091, col. 1).
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to try intratumoral injection of the rMVA vaccine vector with a reasonable expectation of success because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.” One of ordinary skill in the art would have understood the previously known recombinant vaccinia virus vector administration routes, including intratumoral, whereby the ordinary artisan could have pursued the known potential options with a reasonable expectation of success, as demonstrated by Kudo-Saito-1 and Martinet et al. The number of possible administration routes from which to choose is neither astronomical nor insurmountable, and given the guidance of Kudo-Saito-1 it would be only routine experimentation to determine which route yielded the artisan’s desired effect, whereby Kudo-Saito-1 taught that the intratumoral vaccination was superior in inducing antitumor effects as compared to conventional subcutaneous vaccination (e.g. pg 1091, col. 1).
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to combine intratumoral administration with subcutaneous administration of the rMVA vaccine vector with a reasonable expectation of success because Kudo-Saito-1 successfully demonstrated that the combination of subcutaneous and intratumoral administrations of the recombinant vaccinia vaccine vector yielded superior antitumor effects than either route alone.
The term "comprising", per “A method…… comprising a step”, is open-ended and allows for additional, unrecited elements in the claims. MPEP 2111.03 specifically sets forth that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). Instant independent Claim 14 does not exclude or prohibit a subcutaneous administration step of the rMVA to the subject.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 16, Kupper et al disclosed the tumor-associated antigens include MUC-1, CEA, or HER-2 (e.g. [0070]).
The generalized (syn. systemic) T cell-mediated immunity to a local challenge (site of administration) is acquired by systemic dissemination of activated T cells from the local draining lymph node (e.g. [0195]).
Kudo-Saito-1 taught wherein the tumor antigen is CEA (e.g. Abstract).
Kudo-Saito-2 taught wherein the tumor antigen is CEA (e.g. Abstract).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues secondary consideration that intratumoral injection of rMVAs expressing 4-1BBL and a tumor-associated antigen yields a synergistic increase in the immune response, and significantly improved mouse survival, as compared to rMVAs expressing the tumor-associated antigen alone (e.g. Example 2; Figure 1).
Applicant’s argument(s) has been fully considered, but is not persuasive. Those of ordinary skill in the art previously recognized that expression of 4-1BBL significantly enhanced the immune response to the artisan’s antigen of interest (e.g. Kudo-Saito-2), whereby intratumor administration was superior to subcutaneous administration (e.g. Kudo-Saito-1), and whereby those of ordinary skill in the art previously successfully reduced to practice the ability to express 4-1BBL from a viral vector via intratumoral injection (e.g. Martinet et al, Kudo-Saito-2). Thus, Applicant’s observation is not considered to be a surprising or unexpected result.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., significantly improving mouse survival) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Instant claims are directed to a method of stimulating an immune response in a subject, for which the cited prior art fully teaches a reasonable expectation of success for the intratumoral administration of a recombinant vaccinia virus expressing the combination of 4-1BBL and a tumor antigen to achieve.
The Examiner notes that Examples 1-6 fail to disclose the dosage of the rMVA-4-1BBL-Gp70 virus that was administered intratumorally to the mouse subjects from which the argued secondary considerations were achieved.
The Examiner also provides the following reference to rebut applicant’s arguments
regarding the state of the prior art regarding enhanced immune results via intratumoral injection. Note: the reference is not considered a part of the 103 rejection but is solely provided to rebut applicant’s argument(s).
Kudo-Saito et al (Induction of an Antigen Cascade by Diversified Subcutaneous/Intratumoral Vaccination Is Associated with Antitumor Responses, Clin. Cancer Res. 11: 2416-2426, 2005)-- relied upon here as to the state of the art and rebut Appellant’s argument, not a basis of rejection-- is considered relevant prior art for having taught a method of stimulating an immune response in a subject, the method comprising the step of administering via intratumoral injection in said subject a recombinant vaccinia vector cancer vaccine encoding a tumor-associated antigen and at least one immunostimulatory molecule (e.g. Title, Abstract), whereby intratumoral injection of the rMVA expressing a tumor antigen and immunostimulatory molecules yielded significantly superior results relative to subcutaneous injection (e.g. Figures 1-2; pg 2419, “tumor growth was markedly and significantly inhibited”).
Thus, Applicant’s observation is not considered to be a surprising or unexpected result because those of ordinary skill previously recognized intratumoral injection of recombinant vaccinia vector cancer vaccine encoding a tumor-associated antigen and at least one immunostimulatory molecule to achieve superior immune-stimulating responses against the target tumor.
8. Claims 14 and 16 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Robinson et al (WO 17/120577; of record in IDS) in view of Ragonnaud et al (2016; of record) and Schlom et al (U.S. Patent 7,771,715; of record), Kudo-Saito et al (2004; hereafter Kudo-Saito-1; of record), Martinet et al (2002; of record), and Kudo-Saito et al (2006; hereafter Kudo-Saito-2; of record in IDS).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 14, Robinson et al is considered relevant prior art for having disclosed a method of stimulating an immune response in a subject, to wit, a mouse, having a tumor, the method comprising the step(s) of administering to the subject, e.g. via intramuscular, intradermal, or subcutaneous injection, or topically (e.g. pg 5, lines 8-9; pg 31, lines 7-8; pg 31, lines 28-30) a pharmaceutical composition comprising a recombinant MVA virus expressing:
i) a first nucleic acid encoding a tumor-associated antigen (e.g. pg 3, lines 3-10); and
ii) a second nucleic acid encoding a viral matrix protein (e.g. pg 2, lines 26-30).
Robinson et al disclosed the viral matrix protein enhances the immune response (e.g. pg 28, lines 5-6).
Robinson et al do not disclose wherein the rMVA expresses 4-1BBL.
However, prior to the effective filing date of the instantly claimed invention, Ragonnaud et al is considered relevant prior art for having taught a method of stimulating an immune response in a subject, to wit, a mouse, having a tumor, the method comprising the step(s) of administering to the subject, e.g. via subcutaneous injection (e.g. pg 2148, col. 1, Methods, 2.2 Adenoviral immunization) a pharmaceutical composition comprising a recombinant adenovirus expressing:
i) a first nucleic acid encoding a tumor-associated antigen; and
ii) a second nucleic acid encoding 4-1BBL (e.g. pg 2150, Figure 1a).
Ragonnaud et al taught that co-expression of 4-1BBL was previously recognized to successfully enhance immune responses to the artisan’s target antigen, and the vaccine delayed tumor growth in the mouse subject (e.g. Abstract).
Neither Robinson et al nor Ragonnaud et al teach/disclose intratumoral injection of the rMVA.
However, prior to the effective filing date of the instantly claimed invention, Schlom et al is considered relevant prior art for having disclosed a method of stimulating an immune response in a subject, the method comprising the step(s) of administering to the subject a pharmaceutical composition comprising a rMVA virus expressing:
i) a first nucleic acid encoding a tumor-associated antigen; and
ii) a second nucleic acid encoding an immune co-stimulatory molecule (e.g. col. 3, liens 30-34; col. 9, lines 49-51; Figure 21),
wherein the immune co-stimulatory molecule may be 4-1BBL (e.g. col. 3, line 44; col. 15, lines 25-27).
Schlom et al taught wherein the viral vaccine vector may be administered to the subject topically, e.g. scarification, subcutaneously, intramuscularly, or intratumorally (e.g. col. 27, lines 21-23).
Kudo-Saito-1 is considered relevant prior art for having taught a method of stimulating an immune response in a subject, the method comprising the step of administering via intratumoral injection in said subject a recombinant vaccinia vector cancer vaccine encoding a tumor-associated antigen and at least one immunostimulatory molecule (e.g. Title, Abstract). Kudo-Saito-1 taught that the combination of a subcutaneous administration prime and an intratumoral administration boost induced an antitumor response therapy superior to either route individually (e.g. Abstract).
Martinet et al is considered relevant prior art for having taught intratumoral injection of a viral vector expressing 4-1BBL (e.g. Abstract), whereby 4-1BBL was previously recognized in the art to amplify T cell-mediated immunity (e.g. pg 786, col. 2).
Kudo-Saito-2 is considered relevant prior art for having taught a recombinant vaccinia virus expressing 4-1BBL in combination with a recombinant vaccinia virus expressing a tumor antigen, to wit, CEA, whereby the 4-1BBL-expressing virus significantly enhanced the therapeutic effects against CEA-expressing tumors (e.g. Abstract), whereby the combination of the 4-1BBL-expressing virus and the CEA-expressing virus yielded a synergistically greater therapeutic response than the 4-1BBL-expressing virus or the CEA-expressing virus alone (e.g. Figure 2).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a subcutaneous administration of an rMVA vaccine vector, as disclosed by Kupper et al, with intratumoral administration, in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute subcutaneous administration with intratumoral administration in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector because those of ordinary skill in the art had long-recognized the scientific and technical concepts that the subcutaneous administration route may be substituted with intratumoral administration route, as successfully demonstrated by Kudo-Saito-1 and Martinet et al, whereupon Kudo-Saito-1 taught that the intratumoral vaccination was superior in inducing antitumor effects as compared to conventional subcutaneous vaccination (e.g. pg 1091, col. 1).
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to try intratumoral injection of the rMVA vaccine vector with a reasonable expectation of success because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.” One of ordinary skill in the art would have understood the previously known recombinant vaccinia virus vector administration routes, including intratumoral, whereby the ordinary artisan could have pursued the known potential options with a reasonable expectation of success, as demonstrated by Kudo-Saito-1 and Martinet et al. The number of possible administration routes from which to choose is neither astronomical nor insurmountable, and given the guidance of Kudo-Saito-1 it would be only routine experimentation to determine which route yielded the artisan’s desired effect, whereby Kudo-Saito-1 taught that the intratumoral vaccination was superior in inducing antitumor effects as compared to conventional subcutaneous vaccination (e.g. pg 1091, col. 1).
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to combine intratumoral administration with subcutaneous administration of the rMVA vaccine vector with a reasonable expectation of success because Kudo-Saito-1 successfully demonstrated that the combination of subcutaneous and intratumoral administrations of the recombinant vaccinia vaccine vector yielded superior antitumor effects than either route alone.
The term "comprising", per “A method…… comprising a step”, is open-ended and allows for additional, unrecited elements in the claims. MPEP 2111.03 specifically sets forth that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). Instant independent Claim 14 does not exclude or prohibit a subcutaneous administration step of the rMVA to the subject.
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to substitute a first nucleic acid encoding a viral matrix protein to enhance the immune response, as disclosed by Robinson et al, with a second nucleic acid encoding an immuno co-stimulatory molecule, to wit, 4-1BBL, as taught/disclosed by Ragonnaud et al and Schlom et al, in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first nucleic acid encoding a viral matrix protein to enhance the immune response with a second nucleic acid encoding an immuno co-stimulatory molecule, to wit, 4-1BBL, in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector because those of ordinary skill in the art had long-recognized the scientific and technical concepts of:
a) co-expression of 4-1BBL to successfully enhance immune responses to the artisan’s target antigen, and the vaccine delayed tumor growth in the mouse subject (e.g. Ragonnaud et al); and
b) rMVA viruses expressing:
i) a first nucleic acid encoding a tumor-associated antigen; and
ii) a second nucleic acid encoding an immune co-stimulatory molecule, wherein the immune co-stimulatory molecule may be 4-1BBL (e.g. Schlom et al).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 16, Robinson et al disclosed wherein said first nucleic acid encodes carcinoembryonic antigen (CEA) or mucin 1 cell surface associated (MUC-1) (e.g. pg 3, lines 3-10).
Schlom et al disclosed wherein said first nucleic acid encodes carcinoembryonic antigen (CEA), mucin 1 cell surface associated (MUC-1), or human epidermal growth factor receptor 2 (HER-2) (e.g. col. 22, lines 35-60; Figure 7).
Kudo-Saito-1 taught wherein the tumor antigen is CEA (e.g. Abstract).
Kudo-Saito-2 taught wherein the tumor antigen is CEA (e.g. Abstract).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant iterates the above arguments.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner incorporates herein the rebuttals to Applicant’s arguments.
9. Claims 16-17 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Robinson et al (WO 17/120577; of record in IDS) in view of Ragonnaud et al (2016; of record) and Schlom et al (U.S. Patent 7,771,715; of record), Kudo-Saito et al (2004; hereafter Kudo-Saito-1; of record), Martinet et al (2002; of record), and Kudo-Saito et al (2006; hereafter Kudo-Saito-2; of record in IDS), as applied to Claim 14 and 16 above, and in further view of Kraus et al (available online August 30, 2013; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 16, Robinson et al disclosed wherein said first nucleic acid encodes carcinoembryonic antigen (CEA) or mucin 1 cell surface associated (MUC-1) (e.g. pg 3, lines 3-10).
Schlom et al disclosed wherein said first nucleic acid encodes carcinoembryonic antigen (CEA), mucin 1 cell surface associated (MUC-1), or human epidermal growth factor receptor 2 (HER-2) (e.g. col. 22, lines 35-60; Figure 7).
Kudo-Saito-1 taught wherein the tumor antigen is CEA (e.g. Abstract).
Kudo-Saito-2 taught wherein the tumor antigen is CEA (e.g. Abstract).
Neither Robinson et al, Ragonnaud et al, Schlom et al, Kudo-Saito-1, nor Kudo-Saito-2 teach/disclose wherein tumor-associated antigen is a HERV-K envelope protein.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 16-17, Kraus et al is considered relevant prior art for having taught a method of stimulating an immune response in a subject, to wit, mouse, the method comprising the step(s) of administering to the subject, e.g. intramuscular injection (e.g. pg 2, col. 2, Methods, Animal experiments) a pharmaceutical composition comprising a rMVA virus expressing:
i) a first nucleic acid encoding a tumor-associated antigen, wherein the tumor-associated antigen is a HERV-K envelope protein (e.g. pg 2, col. 1, Methods, Generation of recombinant MVA).
Kraus et al taught that enhanced anti-HERV-K-directed immune responses were previously recognized in tumor patients (e.g. Abstract). Because HERV-K is usually not expressed, and immunological tolerance development is unlikely, it is an appropriate target for the development of anti-tumor immunotherapies (e.g. Abstract).
Kraus et al taught wherein the rMVA-HERV-K env vector is able to enhance the HERV-K ENV-specific killing activity of splenocytes in vivo, is a useful target for vaccine development, and offers new treatment opportunities for diverse types of cancer (e.g. Abstract).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first tumor-associated antigen, e.g. CEA, MUC-1, or HER-2, as disclosed by Robinson et al and/or Schlom et al, with a second tumor-associated antigen, to wit, HERV-K envelope protein, as taught by Kraus et al, in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector in a subject suffering from cancer with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first tumor-associated antigen, e.g. CEA, MUC-1, or HER-2, with a second tumor-associated antigen, to wit, HERV-K envelope protein, in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector in a subject suffering from cancer because those of ordinary skill in the art have long-recognized that the tumor-associated antigen encoded by the cancer vaccine is substitutable per the type of cancer, and Kraus et al taught wherein the rMVA-HERV-K env vector is able to enhance the HERV-K ENV-specific killing activity of splenocytes in vivo, is a useful target for vaccine development, and offers new treatment opportunities for diverse types of cancer (e.g. Abstract).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that Kraus et al do not cure the defect of Robinson et al, Ragonnaud et al, and Schlom et al.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner’s response to Applicant's argument(s) regarding Robinson et al, Ragonnaud et al, and Schlom et al are discussed above and incorporated herein. Applicant does not contest the teachings of Kraus et al as applied to the obviousness to substitute a first tumor-associated antigen, e.g. CEA, MUC-1, or HER-2, as disclosed by Robinson et al and/or Schlom et al, with a second tumor-associated antigen, to wit, HERV-K envelope protein, as taught by Kraus et al, in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector in a subject suffering from cancer with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first tumor-associated antigen, e.g. CEA, MUC-1, or HER-2, with a second tumor-associated antigen, to wit, HERV-K envelope protein, in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector in a subject suffering from cancer because those of ordinary skill in the art have long-recognized that the tumor-associated antigen encoded by the cancer vaccine is substitutable per the type of cancer, and Kraus et al taught wherein the rMVA-HERV-K env vector is able to enhance the HERV-K ENV-specific killing activity of splenocytes in vivo, is a useful target for vaccine development, and offers new treatment opportunities for diverse types of cancer (e.g. Abstract).
10. Claims 16-18 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Robinson et al (WO 17/120577; of record in IDS) in view of Ragonnaud et al (2016; of record) and Schlom et al (U.S. Patent 7,771,715; of record), Kudo-Saito et al (2004; hereafter Kudo-Saito-1; of record), Martinet et al (2002; of record), Kudo-Saito et al (2006; hereafter Kudo-Saito-2; of record in IDS), and Kraus et al (available online August 30, 2013; of record), as applied to Claims 14 and 16-17 above, and in further view of Meruelo et al (U.S. 2018/0000912; published January 4, 2018; of record), Guan et al (2011; of record), Florikiewicz (U.S. 2017/0016026; of record), and Weber et al (2011; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claims 16-17, Robinson et al disclosed wherein said first tumor-associated antigen nucleic acid encodes carcinoembryonic antigen (CEA) or mucin 1 cell surface associated (MUC-1) (e.g. pg 3, lines 3-10).
Schlom et al disclosed wherein said first tumor-associated antigen nucleic acid encodes carcinoembryonic antigen (CEA), mucin 1 cell surface associated (MUC-1), or human epidermal growth factor receptor 2 (HER-2) (e.g. col. 22, lines 35-60; Figure 7).
Kudo-Saito-1 taught wherein the tumor antigen is CEA (e.g. Abstract).
Kudo-Saito-2 taught wherein the tumor antigen is CEA (e.g. Abstract).
Kraus et al taught wherein said first tumor-associated antigen nucleic acid encodes a HERV-K envelope protein.
Neither Robinson et al, Schlom et al, Kudo-Saito-1, Kudo-Saito-2, nor Kraus et al teach/disclose wherein the first tumor-associated antigen nucleic acid encodes a folate receptor alpha (syn. FOLR1) and PRAME fusion protein.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 16-18, Meruelo et al is considered relevant prior art for having disclosed a method of stimulating an immune response in a subject, the method comprising the step of administering to the subject a viral expression vector, e.g. rMVA [0148], encoding a polyepitope mRNA encoding multiple tumor-associated antigens (syn. fusion protein), wherein the tumor-associated antigens include PRAME, CEA, HER-2, MUC-1, HERV-K-MEL, TRP-1, TRP-2, PSMA, and/or folate receptor alpha (e.g. [0008]; claim 4; Figure 1a).
Meruelo et al disclosed the polynucleotide may encode multiple epitopes from the same tumor-associated antigen (e.g. [0085]; Table 1, at least five different PRAME epitopes, at least two different folate receptor alpha epitopes).
Guan et al is considered relevant prior art for having taught a DNA vaccine encoding PRAME protein (e.g. pg 93, col. 2, Methods, pVAX-PRAME), which necessarily comprises multiple epitopes from the same tumor-associated protein.
Florikiewicz is considered relevant prior art for having disclosed a method of stimulating an immune response in a subject, the method comprising the step of administering to the subject a DNA vaccine vector encoding a polyepitope mRNA encoding 2-20 tumor-associated antigens (syn. fusion protein; Figure 1, peptide antigen array; [0084]), including tumor-associated antigens from different proteins, e.g. HER-2 and folate receptor alpha (e.g. [0121]), wherein the multiple peptide antigen array includes at least 5 to 24 different folate receptor alpha tumor-associated antigens (e.g. [0113]; Example 10, [0187]) and 4 to 16 different HER-2 tumor-associated antigens (e.g. [0113]; Example 9, [0180]).
Weber et al is considered relevant prior art for having taught a polyepitope nucleic acid antitumor vaccine encoding a fusion protein comprising multiple tumor-associated antigens, wherein the tumor-associated antigens include PRAME and PSMA, which is an art-recognized a folate hydrolase (pg 556, col. 2), as illustrated in Figure 1A.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first nucleic acid encoding a tumor-associated antigen, e.g. CEA, MUC-1, or HER-2, as disclosed by Robinson et al and/or Schlom et al, with a second nucleic acid encoding a fusion protein comprising at least two different tumor-associated antigens from at least two different tumor-associated proteins, e.g. PRAME and folate receptor alpha, in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector in a subject suffering from cancer with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first nucleic acid encoding a tumor-associated antigen, e.g. CEA, MUC-1, or HER-2, with a second nucleic acid encoding a fusion protein comprising at least two different tumor-associated antigens from at least two different tumor-associated proteins, e.g. PRAME and folate receptor alpha, in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector in a subject suffering from cancer because those of ordinary skill in the art previously recognized the scientific and technical concepts that nucleic acid vaccines, including rMVA expression vectors (Meruelo et al) may comprise a nucleic acid the encodes a fusion protein comprising a plurality of tumor-associated antigens, including PRAME tumor antigens (Meruelo et al, Guan et al, Weber et al) and folate receptor alpha tumor antigens (Meruelo et al, Florikiewicz), as successfully demonstrated by Weber et al.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
The folate receptor alpha-PRAME fusion protein is recited at a high level of generality, and the specification fails to disclose an element of criticality for the fusion protein structure, but for that it encode at least one folate receptor alpha tumor-associated antigen and at least one PRAME tumor-associated antigen, and have the ability to stimulate an immune response.
The prior art teaches/discloses that polyepitope fusion proteins comprising multiple art-recognized folate receptor alpha tumor-associated antigens and/or multiple art-recognized PRAME tumor-associated antigens in methods of stimulating an immune response in a cancer subject. The prior art also taught nucleic acid vaccine encoding PRAME protein. Thus, absent evidence to the contrary, such polyepitope fusion proteins, including PRAME protein, would have been reasonably expected by the ordinary artisan to predictably generate an immune response to the folate receptor alpha and PRAME antigens.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that Meruelo et al, Guan et al, Florikiewicz, and Weber et al do not cure the defect of Robinson et al, Ragonnaud et al, and Schlom et al, and Kraus et al.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner’s response to Applicant's argument(s) regarding Robinson et al, Ragonnaud et al, and Schlom et al are discussed above and incorporated herein. Applicant does not contest the teachings of Meruelo et al, Guan et al, Florikiewicz, and Weber et al as applied to the obviousness to substitute a first nucleic acid encoding a tumor-associated antigen, e.g. CEA, MUC-1, or HER-2, as disclosed by Robinson et al and/or Schlom et al, with a second nucleic acid encoding a fusion protein comprising at least two different tumor-associated antigens from at least two different tumor-associated proteins, e.g. PRAME and folate receptor alpha, in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector in a subject suffering from cancer with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first nucleic acid encoding a tumor-associated antigen, e.g. CEA, MUC-1, or HER-2, with a second nucleic acid encoding a fusion protein comprising at least two different tumor-associated antigens from at least two different tumor-associated proteins, e.g. PRAME and folate receptor alpha, in a method of stimulating an immune response to a tumor-associated antigen expressed from a rMVA vector in a subject suffering from cancer because those of ordinary skill in the art previously recognized the scientific and technical concepts that nucleic acid vaccines, including rMVA expression vectors (Meruelo et al) may comprise a nucleic acid the encodes a fusion protein comprising a plurality of tumor-associated antigens, including PRAME tumor antigens (Meruelo et al, Guan et al, Weber et al) and folate receptor alpha tumor antigens (Meruelo et al, Florikiewicz), as successfully demonstrated by Weber et al.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
The folate receptor alpha-PRAME fusion protein is recited at a high level of generality, and the specification fails to disclose an element of criticality for the fusion protein structure, but for that it encode at least one folate receptor alpha tumor-associated antigen and at least one PRAME tumor-associated antigen, and have the ability to stimulate an immune response.
The prior art teaches/discloses that polyepitope fusion proteins comprising multiple art-recognized folate receptor alpha tumor-associated antigens and/or multiple art-recognized PRAME tumor-associated antigens in methods of stimulating an immune response in a cancer subject. The prior art also taught nucleic acid vaccine encoding PRAME protein. Thus, absent evidence to the contrary, such polyepitope fusion proteins, including PRAME protein, would have been reasonably expected by the ordinary artisan to predictably generate an immune response to the folate receptor alpha and PRAME antigens.
Citation of Relevant Prior Art
11. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Nemeckova et al (Combination of Intratumoral injections of vaccinia virus MVA expressing GM-CSF and immunization with DNA vaccine prolongs the survival of mice bearing HPV16 induced tumors with downregulated expression of MHC class I molecules, Neoplasma 54(4): 326-333, 2007) is considered relevant prior art for having taught a method of stimulating an immune response in a subject, the method comprising the step of administering via intratumoral injection in said subject a recombinant MVA vector (e.g. Title; Abstract) encoding an immunostimulatory molecule. Nemeckova et al taught that intratumoral delivery of MVA-GM-CSF changed the local tumor microenvironment and rendered tumors more attractive and better accessible to effector T cells, thereby increasing the cytotoxic T cells counts in the tumors (e.g. Abstract).
Conclusion
12. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEVIN K. HILL whose telephone number is (571)272-8036. The examiner can normally be reached 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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