DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 7, 13-18 and 23-25 are pending and under examination.
Objection to Specification withdrawn
The objection to the specification is withdrawn in view of Applicant’s amendments to the specification.
35 USC § 112(a) rejections withdrawn
The rejections of claims 13-18 for failing to comply with the written description rejection are withdrawn in view of the amendments to claim 7.
35 USC § 103 rejections withdrawn
The rejections of claims 7, 13-18 and 23 under 35 U.S.C. 103 as being unpatentable over Tseng et al (Nature 22:70-77, 2017, IDS) in view of Zitvogel et al (US 2017/0143780, published May 15, 2017) are withdrawn in view of Applicant’s amendments to claim 7,
Objections to Claims
The cancelation of claims 19-22 is not indicated in the amended claim set.
35 USC § 103 rejections maintained
The rejections of claims 7, 13-18 and 23-25 under 35 U.S.C. 103 as being unpatentable over Tseng et al (Nature 22:70-77, 2017, IDS, cited previously) in view of Zitvogel et al (US 2017/0143780, US 2017/0143780, published May 15, 2017, cited previously) in further view of Li et al (US 7,183,262, issued February 27, 2007) and Bakker et al (US 7,550,140, issued June 23, 2009) are maintained.
The claims are drawn to a method for treating cancer comprising administering a Sindbis viral vector comprising a nucleic acid encoding IL-12 further encoding an anrti-OX40 monoclonal antibody comprising a heavy chain comprising the sequence of SEO ID NO:5 and a light chain comprising SEO ID NO:7.
Tseng teaches a method of treating ovarian cancer using a Sindbis viral vector encoding an IL-12 gene (page 72, 2nd column to page 73, 1st column).
Tseng does not specifically disclose administering an antibody to OX40.
Zitvogel disclose a synergistic combination of a Sindbis oncolytic virus and an antibody to OX40 for use for the treatment of proliferative diseases such as ovarian cancer (paragraphs 14, 96, 101, 152,). Zitvogel disclose that the checkpoint modulators may be administered by intravenous, intratumoral, or intraperitoneal route sequentially or simultaneously (paragraphs 17, 145, 146). Zitvogel discloses that the antibody to OX40 may be administered as an antibody or a nucleic acid encoding the antibody (paragraphs 38, 59).
One of ordinary skill in the art would have been motivated to apply Zitvogel’s composition comprising an antibody to OX40 for use for the treatment of proliferative diseases such as ovarian cancer to Tseng’s method of treating ovarian cancer comprising administering a Sindbis viral vector encoding an IL-12 gene because both Tseng and Zitvogel teach methods for treating ovarian cancer with a Sindbis oncolytic virus along with additional immunotherapeutic agents. It would have been prima facie obvious to combine Tseng’s method of treating ovarian cancer comprising administering a Sindbis viral vector encoding an IL-12 gene with Zitvogel’s composition comprising an antibody to OX40 for use for the treatment of ovarian cancer to have a method for treating ovarian cancer comprising administering (a) a Sindbis viral vector and (b) an antibody directed against OX40, or a nucleic acid encoding same. One of ordinary skill in the art would have had a reasonable expectation of success given that the administration of oncolytic viruses and treatment with anti-OX40 to treat cancer were well-known.
Neither Tseng nor Zitvogel disclose the nucleic acid encoding
interleukin-12, or the nucleic acid encoding the anti-OX40 monoclonal antibody comprises the nucleic acid sequence of SEQ ID NO:6 or a nucleic acid sequence the nucleic acid sequence of SEQ ID NO:8 encoding an anti-OX40 antibody light chain.
Li disclose a nucleic acid sequence encoding interleukin 12.
Bakker disclose an anti-OX40 antibody comprising variable heavy chain comprising the amino acid sequence of SEQ ID NO: 5 and variable light chain comprising the amino acid sequence of SEQ ID NO: 7. As indicated in paragraph 12 of the specification, the variable heavy chain comprising the amino acid sequence of SEQ ID NO: 5 is encoded by the nucleic acid sequence of SEQ ID NO:6 and the variable light chain comprising the amino acid sequence of SEQ ID NO: 7 is encoded by the nucleic acid sequence of SEQ ID NO:8.
Paragraph 00012 recites that
The Sindbis viral vector can comprise a nucleic acid encoding an anti-OX40 variable heavy chain comprising the amino acid sequence of SEQ ID NO: 5. The nucleic acid sequence encoding the anti-OX40 variable heavy chain is SEQ ID NO: 6. The Sindbis viral vector can comprise a nucleic acid encoding an anti-OX40 variable light chain comprising the amino acid sequence of SEQ ID NO: 7. The nucleic acid sequence encoding the anti-OX40 variable light chain is SEQ ID NO: 8.
One of ordinary skill in the art would have been motivated to substitute Li’s nucleic acid encoding interleukin 12 for Tseng’s IL-12 molecule and to substitute Bakker specific anti-OX40 antibody comprising variable heavy chain comprising the amino acid sequence of SEQ ID NO: 5 and variable light chain comprising the amino acid sequence of SEQ ID NO: 7 for Zitvogel’s anti-OX40 antibody because these are simple substitutions of one known element for another to obtain predictable results.
To reject a claim based on simple substitution one known element for another to obtain predictable results, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
PNG
media_image1.png
18
19
media_image1.png
Greyscale
(1) a finding that the prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
(2) a finding that the substituted components and their functions were known in the art;
PNG
media_image1.png
18
19
media_image1.png
Greyscale
(3) a finding that one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable; and
PNG
media_image1.png
18
19
media_image1.png
Greyscale
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
Both IL-12 molecule and anti-OX40 molecule were known in the art and substituting one for another would have been predictable. Absent unexpected results it would have been obvious to substitute Bakker specific anti-OX40 antibody comprising variable heavy chain comprising the amino acid sequence of SEQ ID NO: 5 and variable light chain comprising the amino acid sequence of SEQ ID NO: 7 for Zitvogel’s anti-OX40 antibody.
Applicant argues that the section of Tseng et al. only describe ovarian cancer data obtained using SCID mice. As is known in the art, SCID stands for "Severe Combined Immunodeficiency." SCID mice are well known to lack functional T and B lymphocytes due to a mutation which impairs development of T and B cell receptors. Applicant argues that as such, any anti-ovarian cancer effect obtained using the Sindbis virus encoding IL-12 described in Tseng et al. is not reliable for predicting any anti-cancer effect in an ovarian or other type of cancer patient setting where an intact immune system is present. Applicant argues that these distinctions are relevant in view of the present disclosure which demonstrates in immunocompetent mice (FVB/NJ and BALB/c mice) that combined use of IL-12 and an anti-OX40 antibody activates tumor immunity against low immunogenic tumors through the metabolic rewiring of T cells into
highly activated effector cells.
Applicant argues that the disclosure also demonstrates that IL-12 in combination with an anti-OX40 antibody induces a marked immune cell infiltration into the tumor
microenvironment. Applicant argues that new claim 24 specifies that the Sindbis viral vector induces an immune response in a tumor associated antigen (TAA) nonspecific manner. Applicant argues that new claim 25 specifies that the Sindbis viral vector alters a tumor microenvironment by promoting T cell infiltration of the tumor microenvironment. Applicant argues that these immunological, anti-cancer responses could not have appeared in SCID mice.
Applicant’s arguments have been considered but are not persuasive. In response to applicant's arguments against Tseng individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The claims are drawn to a method for treating cancer comprising administering a Sindbis viral vector comprising a nucleic acid encoding IL-12 further encoding an anrti-OX40 monoclonal antibody comprising a heavy chain comprising the sequence of SEQ ID NO:5 and a light chain comprising SEO ID NO:7.
Tseng teaches a method of treating ovarian cancer using a Sindbis viral vector encoding an IL-12 gene (page 72, 2nd column to page 73, 1st column). Tseng discloses Sindbis viral vectors systemically and specifically infect tumor cells (Abstract). Tseng discloses that a single intraperitoneal treatment allows the vectors to target most tumor cells, as demonstrated by immunohistochemistry, without infecting normal cells (Id). Tseng further disclose that Sindbis infection is sufficient to induce complete tumor regression. Tseng document the anti-tumor specificity of a vector that systemically targets and eradicates tumor cells throughout the body without adverse effects (Id). Thus, based on Tseng it would have been obvious to administer a Sindbis viral vector comprising a nucleic acid encoding IL-12 to a cancer patient.
It is not clear the relevance of the animal model used in Tseng. Tseng states that Sindbis viral vector comprising a nucleic acid encoding IL-12 was capable of eradicating tumor cells without effecting non-tumor cells. IL-12 is known to activate T cells and NK cells and thus it is likely the Sindbis viral vector comprising a nucleic acid encoding IL-12 would have an enhanced effect on cancer patients with a functional immune response.
Applicant appears to be arguing that the mechanism of action from the combined use of IL-12 and an anti-OX40 antibody through the induction of tumor immunity against low immunogenic tumors through the metabolic rewiring of T cells into highly activated effector cells would result in the enhanced effectiveness of the Sindbis viral vector comprising a nucleic acid encoding IL-12 and anti-OX-40 antibody. However, Applicants have not demonstrated unexpected results from their determination of the mechanism of action from the administration of the Sindbis viral vector comprising a nucleic acid encoding IL-12 and anti-OX-40 antibody. There would be sufficient motivation from the results of Tseng to administer a Sindbis viral vector comprising a nucleic acid encoding IL-12 to a cancer patient.
In response to Applicant’s argument that any anti-ovarian cancer effect obtained using the Sindbis virus encoding IL-12 described in Tseng is not reliable for predicting any anti-cancer effect in an ovarian or other type of cancer patient setting where an intact immune system is present, it is not clear why one of skill in the art would look at Tseng and not think that the administration of the Sindbis viral vector comprising a nucleic acid encoding IL-12 would not be capable of treating a cancer patient. Tseng discloses that they demonstrate the anti-tumor specificity of a vector that targets and eradicates tumor cells throughout the body without adverse effects.
Applicant further argues that the amended claims specify that the Sindbis viral vector encodes both the IL-12 and the anti-OX40 antibody. Applicant argues that this configuration is not taught or even suggested in Tseng et al. or Zitvogel. Applicant argues that with respect to Zitvogel, this reference merely mentions "Sinbis" along with many other oncolytic virus families from widely divergent virus types, but no Sindbis construct was tested in any experiments in Zitvogel. Instead, all of the data in this reference were obtained using a virus known as WRTG 17137, which is a double
stranded DNA pox virus. Zitvogel mentions an anti-OX40 along with many other receptor agonists. But only anti-PD1 and anti-CTLA4 antibodies were tested in Zitvogel in combination with WRTG 17137. Applicant argues that one skilled in the art could not
reasonably expect that use of a Sindbis viral vector that encodes both the IL-12 and the anti-OX40 antibody would produce the immunological anti-cancer effects that are now recited in the claims.
Applicant’s arguments have been considered but are not persuasive. While the examples in Zitvogel indeed use the WRTG 17137 viral construct rather than a Sindbis viral vector, a prior art reference is relevant for all its teachings, not only its examples. Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989) (holding that both preferred and unpreferred embodiments must be considered). In addition, Applicants point to narrow embodiments which are not the sum total of information conveyed by each. Art is art, not only for what it expressly teaches, but also for what it would reasonably suggest to the skilled artisan, including alternative or non-preferred embodiments. MPEP § 2123. In this case, Zitvogel teaches that Sindbis viral vector is a vector that is suitable for use in its invention. A "specification need not contain a working example if the invention is otherwise disclosed in such a manner that one skilled in the art will be able to practice it without an undue amount of experimentation." In re Borkowski, 422 F.2d 904, 908 (CCPA 1970). Zitvogel discloses the oncolytic virus Sinbis virus and the immune ch4ckpoint modulator. OX40 for the treatment of cancer.
Also, it is noted that preferred embodiments do not constitute a teaching away from nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ
423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994)
Tseng teaches a method of treating ovarian cancer using a Sindbis viral vector encoding an IL-12 gene Zitvogel disclose a synergistic combination of a Sindbis oncolytic virus and an antibody to OX40 for use for the treatment of proliferative diseases such as ovarian cancer. Zitvogel discloses that the antibody to OX40 may be administered as an antibody or a nucleic acid encoding the antibody. Thus, all the limitations are present in the art and as discussed previously, there is motivation to combine Tseng and Zitvogel. Absent unexpected results, it would have been prima facie obvious to combine Tseng and Zitvogel to have a method for treating cancer comprising administering a Sindbis viral vector comprising a nucleic acid encoding IL-12 further encoding an anrti-OX40 monoclonal antibody comprising a heavy chain comprising the sequence of SEQ ID NO:5 and a light chain comprising SEO ID NO:7.
Regarding the interpretive “wherein” clauses recited in claims 24 and 25 (“wherein the Sindbis viral vector induces an immune response in a tumor associated antigen (TAA) nonspecific manner” and “wherein the Sindbis viral vector alters a tumor microenvironment by promoting T cell infiltration of the tumor microenvironment”), the clause does not recite any additional active method steps, but simply states a characterization or conclusion of the results of those steps. Therefore, the “wherein” clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171, 26 USPQ2d 1018, 1023 (Fed Cir. 1993) (“A ‘whereby’ clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim.”). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) (“A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.”). The administration of a Sindbis viral vector comprising a nucleic acid encoding IL-12 and an anrti-OX40 monoclonal antibody to a cancer patient would necessarily alter a tumor microenvironment by promoting T cell infiltration of the tumor microenvironment and induces an immune response in a TAA nonspecific manner.
US-10-517-941A-2
(NOTE: this sequence has 1 duplicate in the database searched)
Sequence 2, US/10517941A
Patent No. 7550140
GENERAL INFORMATION
APPLICANT: Crucell Holland B.V.
APPLICANT: Bakker, Alexander B.H.
APPLICANT: Meester-Rood, Pauline M.L.
APPLICANT: Bakker, Adrianus Q.
TITLE OF INVENTION: AGONISTIC BINDING MOLECULES TO THE HUMAN OX40 RECEPTOR
FILE REFERENCE: 0077 WO 00 ORD
CURRENT APPLICATION NUMBER: US/10/517,941A
CURRENT FILING DATE: 2004-12-13
PRIOR APPLICATION NUMBER: PCT/NL02/00389
PRIOR FILING DATE: 2002-06-13
NUMBER OF SEQ ID NOS: 54
SEQ ID NO 2
LENGTH: 255
SEQ ID NO:5
Query Match 100.0%; Score 637; Length 255;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MAEVQLVESGGGLVQPGGSLRLSCAASGFTFSNYTMNWVRQAPGKGLEWVSAISGSGGST 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MAEVQLVESGGGLVQPGGSLRLSCAASGFTFSNYTMNWVRQAPGKGLEWVSAISGSGGST 60
Qy 61 YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRYSQVHYALDYWGQGTLVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRYSQVHYALDYWGQGTLVT 120
Qy 121 V 121
|
Db 121 V 121
SEQ ID NO:7
Query Match 100.0%; Score 312; Length 219;
Best Local Similarity 100.0%;
Matches 59; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPDSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKAGQSPQLLIYLGSNR 59
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPDSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKAGQSPQLLIYLGSNR 59
Summary
Claims 7, 13-18 and 23-25 stand rejected
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 Mark Halvorson whose telephone number is (571) 272-6539. The examiner can normally be reached on Monday through Friday from 9:00 am to 6:00 pm.. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Janet Epps-Smith, can be reached at (571) 272-0757. The fax phone number for this Art Unit is (571) 273-8300.
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.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MARK HALVORSON/Primary Examiner, Art Unit 1646