tgDETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
The amended claims filed 04/15//2026 are acknowledged and entered.
Claims 1, 3-6, 8, 10, 14, and 19-20 have been amended
Claims 16, 17, 24, and 25 are withdrawn.
Claims 1-15, 18-23 are pending and examined on their merits.
Response to Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Claim Rejections - 35 USC § 112 withdrawn
1. The rejections for claims 3-6, 8, 14, 19-20 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of claims 3-6, 8, 14, 19-20 being amended.
2. The rejection for claim 18 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of Applicant’s arguments.
3. The rejections for claims 6 and 8 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ),), second paragraph, as being indefinite is withdrawn in view of claims 6 and 8 being amended.
4. The rejection for claim 10 under 35 U.S.C. 112(d) or 35 U.S.C. 112 (pre-AIA ), 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of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn in view of claim 10, being amended.
Claim Rejections - 35 USC § 103 - Maintained
6. Claims 1-15 and 18-23 remain rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Bachman (previously cited) in view of Attar (previously cited) and Tang (previously cited).
Applicant’s arguments have been fully considered and are not persuasive. Therefore, the rejections are maintained.
Applicant’s Arguments:
- (a) The claimed methods exhibit unexpected and superior results
The pending claims are directed to methods of treating a myeloproliferative disease, by administering two or more vaccines comprising GAd20 viruses and one or more vaccines comprising a MVA virus to generate mutCALR- and/or mutJAK2-specific T-cell responses in the subject.
The specified dosing regimen generated a surprisingly stronger immune response as compared to other dosing regimens. Example 1 shows that a single GAd20 vaccine generated an immune response in 6 of 20 subjects, two GAd20 vaccines generated an immune response in 11 of 20 subjects (FIG. 2), and two GAd20 vaccines followed by administration of an MVA vaccine generated an immune response in 16 of 20 subjects (FIG 3). Example 1 also shows that two administrations of a GAd20 vaccine followed by one administration of an MVA vaccine increased the magnitude of antigen-specific T cell response 2.4-fold higher at week 11 (FIG. 3) as compared to subjects that did not receive the MVA vaccine (FIG. 2). These results demonstrate that the immune response generated from the administration of two GAd20 vaccines is unexpectedly better than the immune response generated from the administration of a single GAd20 vaccine, and administration of the MVA vaccine increases the antigen-specific T cell response generated by two GAd20 vaccines.
Examiner’s Response to arguments: Applicant’s arguments have been carefully considered but are not found persuasive.
Regarding the specified dosing regimen, Bachman teaches that GAd20 and MVA can be administered one or more times to the subject, which encompasses the required two or more times for GAd20 and one or more times for MVA. It would further be obvious with that the compound dosages in a composition are clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages." (Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 2.
A showing of unexpected results (a clinical breakthrough) must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements that claimed compound possesses unusually low immune response or unexpected biological activity that is unsupported by comparative data held insufficient to overcome prima facie case of obviousness). MPEP § 2145. A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue.” In re Corkill, 711 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). MPEP 716.02 (a). The evidence relied * > upon < should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). MPEP 716.02 (b). Applicant must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). MPEP 716.02 (b). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c). Applicant has failed to provide evidence of unexpected results. The data only shows an additive effect, which would be expected, and not a synergistic effect, which may be unexpected if supported by statistical analysis. In other words, a single dose generates immune response in 6 out of 20 subjects. Doubling the dose, doubles the results (11 out of 20 subjects). Tripling the dose (even if one vaccine is built using a different vector, the insert is the same), triples the results (16 out of 20 subjects). In response to applicant argument of additive results being unexpected results, Wiesenthal, (Human Tumor Assay Journal, on-line at (http://weisenthal.org/synergy1.htm, March 14, 2012) discusses the question of synergy between drug combinations and diseases. Most "classic" drug combinations are only additive or are, at most, minimally synergistic and therefore an additive effect is an expected result (entire article). Applicant has not provided an statistical analysis to show the reproducibility of these results or that the observed results are greater than what one of ordinary skill in the art would routinely expect since multiple doses of vaccines are administered. Evidence of is results is not evidence of unexpected results (greater than expected results). Applicant has failed to provide evidence of such clinical breakthrough.
Applicant’s Arguments:
(b) The cited references fail to teach or suggest the claimed methods.
In an attempt to arrive at the claimed methods, the Office combines Bachman with Attar and Tang, but this combination of references does not render the claims obvious for at least the following reasons.
The Office relies upon Bachman and Attar for their purported disclosure of methods of treating myeloproliferative disease in a subject comprising administering a GAd20 virus and a MVA virus comprising the instantly claimed sequences. The pending claims, however, require a specific treatment regimen comprising two or more vaccines comprising a GAd20 virus and one or more vaccines comprising an MVA virus that is not taught or suggested by Bachman or Attar.
Additionally, Bachman teaches treating prostate cancer with prostate cancer associated
neoantigens, while Attar teaches treating a subject harboring JAK2 and/or CALR mutations. One of ordinary skill in the art would not have had a reasonable expectation of success in combining the methods of Bachman and Attar because these methods use different neoantigens to treat different indications.
Tang does not cure the deficiencies of Bachman and Attar. The Office relies upon Tang for its purported disclosure of the doses of anti-CTLA4 or anti-PD 1 antibodies. Tang is completely silent on methods of treating prostate cancer and treatment regimens comprising vaccines, let alone the specific treatment regimen of the pending claims. The Office has not established that Bachman, alone or in combination with Attar and Tang, would have taught or suggested the use of two vaccines comprising a GAd20 virus and one vaccine comprising a MVA virus for the treatment of a myeloproliferative disease. Moreover, the Office fails to explain why one of ordinary skill in the art would have been motivated to randomly select the dosing regimen specified by the claims from the cited references without the use of Applicant's claims as a road map
Examiner’s Response to arguments: Applicant’s arguments have been carefully considered but are not found persuasive.
One cannot show nonobviousness by attacking references individually (as is the case above) 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). Bachman teaches vectors, host cells, recombinant virus particles, vaccines comprising antigens and methods of making and using them. That is, GAd20 and MVA are vaccine vectors and thus can comprise any insert, including several types of antigen and any vector, if it is able to deliver antigen X successfully, will also deliver any other antigen successfully because the delivery is a function of the vector and not of the antigen. Bachman teaches that GAd20 and MVA can be administered one or more times to the subject, which encompasses the required two or more times for GAd20 and one or more times for MVA. Attar teaches the insert for the polycythemia vera (PV) comprising the amino acid SEQ ID NO: 12 which is 100% identical to instant application SEQ ID NO; 1. Attar teaches the same vaccine vectors GAd20 (claim 14) and MVA (Attar claim 15) that are taught by Bachman and recited in the instant application. Tang teaches that the dose/response relationships for a PD-1 inhibitor antibody and the doses for a CTLA-4 antibody. The combination of these three references teach the claimed invention.
In response to applicant’s argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning (the mentioned “road map”), it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As discussed below, there is ample motivation to combine the references independent of the inherent feature.
Applicant has not sufficiently described why there is no prima facie case for obviousness. See discussion in the previous Office Action for more details regarding the teachings of Bachman, Attar and Tang relevant to the rejection under 35 U.S.C. 103 and the motivation to combine these references.
6. Claims 1-15 and 18-23 remain rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Bachman (previously cited), in view of Andersen (previously cited), Lim (previously cited), Ayyagar (previously cited) and Tang (previously cited).
Applicant’s arguments have been fully considered and are not persuasive. Therefore, the rejections are maintained.
Applicant’s Arguments: The Office relies upon seven disparate sequence fragments from three different cited references (Andersen, Lim, and Ayyagar) to allegedly arrive at SEQ ID NO: 1 of the pending claims (See, Sequence Alignments in Action at p. 13-14). However, one of ordinary skill in art would not pick and choose various parts of the different sequences to arrive at the claimed SEQ ID NO: 1, let alone the specific administration regimen.
Andersen teaches the exon 9 mutant CALR epitope and the JAK2V671 epitope, however Andersen does not teach or suggest vaccines comprising a GAd20 virus or an MVA virus.
Lim teaches CALR and JAK2 mutations and associated disease pathology. Lim does not teach or suggest a vaccine comprising GAd20 and MVA viruses for treating a myeloproliferative disease.
Ayyagar merely teaches vaccines targeting SARS-Cov2. Ayyagar does not teach or
suggest a vaccine comprising GAd20 and MVA viruses for treating a myeloproliferative disease.
Thus, combining the teachings of Bachman, Tang, Andersen, Lim, and Ayyagar would not have provided a reasonable expectation of success because there is nothing to suggest that administering two or more vaccines comprising a GAd20 virus comprising a nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 1 and one or more vaccines comprising a MVA virus comprising a nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 1 would achieve the unexpectedly superior immune response discussed in detail above.
The Office fails to indicate how, in the absence of Applicant's disclosure, those of
ordinary skill in the art would have arrived at the claimed methods. Even if, for example, one of ordinary skill in the art would have combined these five references, which applicant does not concede they would have done, that combination of references still would not have taught or even suggested the claimed methods. One of ordinary skill in the art would have still needed some teaching, suggestion, or other motivation to arrive at the claimed methods. The Office
improperly relies upon Applicant's own disclosure for this motivation.
Examiner’s Response to arguments: Applicant’s arguments have been carefully considered but are not found persuasive.
Applicant is reminded that Attar, as discussed above, teaches SEQ ID NO: 12 which is 100% identical to SEQ ID NO: 1. Andersen, Lim, and Ayyagar sequences are cited to “dissect” the different epitopes (JAK2, CALR and the linker) of SEQ ID 1 with the purpose of discussing the involvement of these epitopes in myeloproliferative disorders. Therefore, the sequences taught by Andersen, Lim, and Ayyagar are not “disparate” since they share the same treatment purpose (treatment of myeloproliferative diseases). Andersen, Lim, and Ayyagar together “reconstruct” SEQ ID NO:1 which is also taught by Attar in its entirety.
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 combined teachings of Bachman, Attar and Tang have been discussed above including the vaccines comprising a GAd20 virus or an MVA virus, the results of the immune response and SEQ ID NO: 1. Andersen teaches the use of peptides derived from JAK2 and CALR genes for the treatment of myeloproliferative neoplasms, including polycythemia vera, via a vaccine composition. These peptides are found in SEQ ID NO: 1. Lim teaches a CALR sequence that comprises the second CALR epitope of instant SEQ ID NO: 1 and Ayyagar teaches that the AAY (Ala-Ala-Tyr) linker found in SEQ ID NO: 1. As explained in the previous action, These three references in combination teach the sequence to be inserted into the vaccine vectors of Bachman. It was known in the art that several epitope targeting CARL and JAK2 would be useful in the treatment of myeloproliferative diseases such as PV, so it is obvious to combine them in the same therapy regimen to achieve that purpose. The monotherapy treatment (JAK2 or CALR individually) renders the combination therapy obvious. See MPEP § 2144.06. Art Recognized Equivalence for the Same Purpose [R-01.2024]; I. Combining Equivalents Known For The Same Purpose. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). The art also discloses the same linker and it would be obvious to link both peptides using a linker, especially if such linker would help reducing the junctional immunogenicity and increasing the immunogenicity of multi-epitope vaccines.
In addition, linking these epitopes with the AAY cleavage site for the proteasomes would help reducing the junctional immunogenicity and increasing the immunogenicity of multi-epitope vaccines as taught by Ayyagar. These AAY-linked amino acid sequences encoding CALR and JAK2 epitopes are identical to instant SEQ ID NO: 1. When the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established (See MPEP 2112.01. I).
In response to applicant’s argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As discussed above, there is ample motivation to combine the references independent of the inherent feature.
Applicant has not sufficiently described why there is no prima facie case for obviousness. See discussion in the previous Office Action for more details regarding the teachings of Andersen, Lim and Ayyagar relevant to the rejection under 35 U.S.C. 103 and the motivation to combine these references.
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
Double Patenting- Maintained
Claims 1, 2, 7, 9, 10-13, 15-17 (16 and 17 are now withdrawn) remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 8, 12-16, 18, 20, 21, 23-29 of issued patent No. US 11,793,843 B2 (reference patent), in view of Attar, Tang, Andersen, Lim, and Ayyagar.
Claims 1-14 and 18-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending application No. 18/080,634 (reference application), in view of Attar, Andersen, Lim and Ayyagar
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 and 15 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11, 15-16, 24 of copending application No. US 18/663,981, in view of Bachman.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Arguments:
Claims 1, 2, 7, 9, 10-13, and 15-17 stand rejected for non-statutory double patenting as being unpatentable over claims 1, 4, 8, 12-16, 18, 20, 21 and 23-29 of U.S. Patent No. 11,793,843 (Bachman), in view of Attar, in view of Tang, in view Andersen, in view of Lim, and further in view of Ayyagar. (Action at p. 18). Applicant respectfully disagrees for at least the reason that the cited references do not teach or suggest the specific dosing regimen specified by the pending claims.
Claims 1-14 and 18-22 stand provisionally rejected for non-statutory double patenting as being unpatentable over claims 1-19 of copending U.S. Application No. 18/080,634. (Action at p. 19). Applicant respectfully disagrees for at least the reason that U.S. 18/080,634 does not teach or suggest the specific dosing regimen specified by the pending claims.
Claims 1 and 15 stand provisionally rejected for non-statutory double patenting as being unpatentable over claims 11, 15-16 and 24 of copending U.S. Application No. 18/663,981 in view of Bachman. (Action at p. 20). Applicant respectfully disagrees for at least the reason that U.S. 18/663,981 and Bachman do not teach or suggest the specific dosing regimen specified by the pending claims.
Examiner’s Response to arguments:
Applicant’s arguments have been carefully considered but are not found persuasive.
As discussed above, the references do teach the specific dosing regimen specified by the pending claims.
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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