DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
The amended claims filed 01/15/2016 are acknowledged and entered.
Claims 2, 14 and 17 have been amended
Claims 1, 4, 7, 8, 13, 15, 16, 19, 20, 22-30, 32, 33, 35, 36, and 38-40 are cancelled
Claims 2, 3, 5, 6, 9-12, 14, 17, 18, 21, 31, 34, and 37 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 Objections
1. Claims 2, 6, 9, 11 and 21 are objected because the only periods allowed in a claim are those that follow abbreviations and at the end of a claim, as stated in MPEP § 608.01(m). The periods to be removed are those in “a.”, “b.”, “c.” and “d.”
2. Claim 11 is objected because it recites the limitation: “…wherein the pediatric subject is: (a) 6 months to less than 36 months of age; (b) 3 years to less than 5 years of age; (c) 5 years to less than 9 years of age; and/or (d) 9 years to less than 18 years of age.”. The term, “and/or” is confusing because the pediatric subject cannot be all those age choices at the same time
Rejections Maintained
Claim Rejections - 35 USC § 103 - Maintained
Claims 2, 3, 5, 6, 9-12, 14, 17, 18, 21, 31, and 34 (claim 13 has been deleted) remain rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Bekkat-Berkani (previously cited) and Robertson (previously cited) in view of NCT03282240 (previously cited), NCT03698279 (previously cited) and Chung (previously cited).
Applicant’s arguments have been fully considered and are not persuasive. Therefore, the rejections are maintained.
Applicant’s Arguments: Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
- (a) Applicant amended claim 2 to recite that "the previously unvaccinated subject is provided two doses of vaccine." None of the cited references -Bekkat-Berkani, Robertson, NCT03282240, NCT03698279, and Chung - disclose or suggest administering two doses of a high-dose quadrivalent influenza vaccine (QIV-HD) to a previously unvaccinated pediatric subject.
Based on the cited references, one of ordinary skill in the art would not have been able to predict that a high-dose quadrivalent influenza vaccine would be safe and effective in pediatric subjects aged 6 months to less than 18 years.
Bekkat-Berkani concerns a standard dose quadrivalent influenza vaccine (QIV-SD), (SD = standard dose) with a maximum amount of 15µg/strain hemagglutinin (HA) antigen per dose, for use in individuals aged 6 months and up, and would not inform one of ordinary skill in the art whether vaccines with two, three, and even four times as much hemagglutinin antigen (120 µg, 180 µg, or 240 µg per dose, respectively) would be safe and effective in pediatric subjects.
Robertson teaches administering 180 µg total hemagglutinin antigen to adults older than 65.
NCT03282240 discloses administering a high but undisclosed amount of total hemagglutinin antigen to adults older than 65.
Moreover, pediatric subjects and adults older than 65 show reduced responsiveness to influenza vaccination compared to adults for different reasons. In adults older than 65, poor vaccine responsiveness is likely due to an age-related decline in immune functions, such as far fewer naive B cells, fewer germinal center reactions, and diminished CD4 helper T cell function. Id. In contrast, in infants and young children, poor vaccine responsiveness may be attributed to an immature immune system associated with lower BCR activation, different cytokine milieu during priming (i.e., less Th1-like, more anti-inflammatory), and reduced persistence of long-lived plasma cells in the bone marrow. Id. Therefore, teachings regarding doses for adults older than 65 would not have been understood to be relevant to pediatric subjects. For at least these reasons, the above references do not inform one of ordinary skill in the art whether high dose quadrivalent influenza vaccines would be safe and effective in pediatric subjects, much less in previously unvaccinated subjects and in two doses.
- (b) The present application shows that administration of two doses of QIV-HD is more effective than administration of two doses of standard-dose QIV vaccine in previously unvaccinated pediatric subjects. Example 1 and Example 2 in the present application describe the protocol for and contain results from a phase II, randomized, modified double-blind, active- controlled, multi-center study conducted in 665 children 6 months to 17 years of age to evaluate the safety and immunogenicity of 3 dosages of QIV-HD influenza vaccine administered by intramuscular route versus QIV-SD influenza vaccine. The different dosages comprised HA in the following amounts: 1) 30 µg HA/strain (QIV-HD); 2) 45 µg HA/strain (QIV-HD); 3) 60 µg HA/strain (QIV-HD); or 4) 15 µg HA/strain (standard dose, "QIV-SD"). In the clinical study in Example 1 and 2 the claimed QIV-HD vaccines were shown to be more effective than QIV-SD vaccines when measured in multiple ways such as:
- The geometric mean titer (GMT) - higher seroneutralization GMT against multiple strains as compared to vaccination with a QIV-SD vaccine and higher GMTs after the second dose compared to QIV-SD post-second dose
- Hemagglutination (HAI) assay and the seroconversion rate by HAI method. The claimed QIV-HD vaccines were more effective than QIV-SD vaccines.
- The claimed QIV-HD vaccines were also more effective than QIV-SD vaccines when measured by the seroconversion rate by HAI method. Administration of two doses of the claimed QIV-HD vaccines to previously unvaccinated subjects aged 6 months to less than 36 months also resulted in higher seroconversion rates against multiple strains as compared to vaccination with two doses of a QIV-SD vaccine.
- The claimed QIV-HD vaccines were not only more effective than QIV-SD vaccines, they were also safe. It was not predictable that, despite having two times, three times, and four times the total antigen amount of compared to the QIV-SD vaccines, respectively, vaccination with the 30, 45, and 60 ug dose QIV-HD formulations would be safe and well-tolerated among children 6 months to less than 18 years of age, with no safety concerns identified. Moreover, reactogenicity did not increase after a second dose was administered, compared to the reactogenicity after the first dose was administered, in subjects who received 2 doses of study vaccine approximately 28 days apart.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive.
- Regarding (a), the addition in claims 2 and 14 of the "the previously unvaccinated subject is provided two doses of vaccine." limitation previously found in claim 17 is found obvious in view of the cited prior art as previously discussed in the Non-final Action dated 10/16/2025. Specifically, NCT03698279 teaches a clinical study design for a High-Dose Quadrivalent Influenza Vaccine (QIV-HD) in Children 6 Months to 17 Years of Age where all arms include participants for whom 2 doses of influenza vaccine were recommended and administered at Day 28. The highest dose given in the study is QIV-HD 60 µg HA/strain, which is the maximum dose of claim 2. Doses about two, three, and even four times higher than the 60 µg HA/strain are not found as limitations in the instant claims, and are therefore not considered. In addition, 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). Whereas (1) Bekkat-Berkani teaches a QIV-SD vaccine, for use in individuals aged 6 months and up, (2) Robertson teaches a trivalent, inactivated, split-virus influenza vaccine (IIV3-HD) indicated for use in adults, 65 or older, containing 60 µg HA of each of 3 influenza strain, (3) NCT03282240 teaches administering a QIV-HD vaccine to adults older than 65 (4) NCT03698279 teaches a clinical study design for a QIV-HD (including 60 µg HA/strain) vaccine in children 6 months to 17 years of age and Chung teaches that 63% of children and adolescents and 45% of adults in the United States were vaccinated against influenza during the 2018–2019 season implying that 47% of children and adolescents are unvaccinated. (Since Bekkat-Berkani, Robertson, NCT03282240 and NCT03698279 do not select subjects based on their previous vaccination status, it would be obvious to one skill in the art that a similar percentage of unvaccinated subject would be represented in the trials, and thus unvaccinated subjects were included in the trials). As discussed previously, the prior art combination teaches vaccination of children 6 months to 17 years of age and for adults older than 65 and doses of QIV-HD 60 µg HA/strain, including a second dose. Optimizing the administered dose, or the number of doses or the days between doses is a routine practice that would be obvious to employ. It would have been obvious to combine the above cited references to obtained the claimed invention. There are no limitations in the instant claims reciting reduced responsiveness to influenza vaccination or differences in the immune system between patients. Applicant has not sufficiently described why there is no prima facie case for obviousness.
It is noted however that efficacy and safety measurements in a patient population in a clinical trial are not required for obviousness. These measurements are data obtained after a method is performed. Therefore, there is no need for such data here from the prior art. Furthermore, some efficacy and safety outcomes are expected owed to the fact that clinical trials are performed with the agents of instant claims and their efficacy and safety profiles has also been tested in preclinical studies. Furthermore, as highlighted in a recent decision by the Federal Circuit in Janssen Pharmaceuticals, Inc v. Teva Pharmaceuticals USA, Inc (Case: 22-1258, Decided 04/01/2024), a court should not emphasize a protocol’s lack of results and also fail to consider that the art would fairly suggest to POSA (Pg. 22, Paragraph, second). Again, the clinical trial would suggest to POSA sufficient safety and efficacy to render obvious the claims, particularly when the drugs of the obvious method are already used to treat the target patients as discussed on record. This was also highlighted in the decision above as the court in error did not discuss evidence that paliperidone was already on the market and prescribed to patients in need of schizophrenia treatment (Pg. 22, Paragraph, second). Also, the claims language treating a disease does not import any additional efficacy limitations or safety limitations and the court declined to insert the FDA’s responsibilities into claims (Pg. 22, Paragraph, first). There is no requirement in patent law that POSA be motivated to develop the claimed invention based on a rationale that forms the basis for FDA approval (Pg. 23, Paragraph, first). Therefore, it is clear that no specific safety or efficacy data obtained from a patient population enrolled in "a" clinical trial considered prior art to the claimed invention is required.
- Regarding (b), applicant argues that administration of two doses of QIV-HD is more effective than administration of two doses of standard-dose QIV vaccine in previously unvaccinated pediatric subjects. This is not persuasive because the data discussed in the drawings may show some improvement but either there is no statistical analysis or the statistical analysis may not be significant. For example, Fig. 5 shows two doses of QIV-HD (60 µg) administered one month apart in previously unvaccinated subjects 6 months to less than 36 months of age generated significantly higher GMTs after the second dose compared to QIV-SD post-second dose. However, the data shows the individual influenza strains and not the four strains combined in one administration. Of the four strains, B/Victoria and B/Yamagata show a clear overlap between the standard deviation values, and the standard deviation values for A/H3N2 are close. It does not appear that there is a statistically significant difference between the various treatments. Therefore we do not know if the combination of the four strains at a QIV-HD dose (as recited in the claims) would result in a statistically significant improvement over the combination of the four strains at a QIV-SD dose. Other figures also show data without the combination of the four strains at a QIV-HD dose, or without standard deviation data (Figs. 6 A-D, 11A-B and 12A-E, for reactogenicity) or with overlapping standard deviation ranges and therefore it is not possible to asses a statistically significant difference for those values. Moreover, there is no comparison between the claimed vaccine and the NCT03698279 study which includes a QIV-HD in a pediatric population or between the claimed vaccine with any other cited reference.
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A showing of unexpected results (for example, 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 as discussed above. Evidence of results already described in the art is not evidence of unexpected results (that is, greater than expected results). A person skilled in the art would have expected an improved effectiveness outcome with an increase dose and with an increase in the number of doses to be administered and when optimizing these parameters. Applicant has failed to provide evidence of such clinical breakthrough.
Claims 2, 21 and 37 remain rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Bekkat-Berkani and Robertson in view of NCT03698279, Chung and NCT00112112 (previously cited).
Applicant’s arguments have been fully considered and are not persuasive. Therefore, the rejections are maintained.
Applicant’s Arguments: Applicant argues that none of the cited references: Bekkat-Berkani, Robertson, NCT03282240, NCT03698279, Chung, and NCT00112112 disclose administering two doses of a high-dose quadrivalent influenza vaccine (QIV-HD) to a previously unvaccinated pediatric subject. Therefore, for the reasons discussed above for claims 2, 3, 5, 6, 9-14, 17, 18, 21, 31, and 34, claims 2, 21, and 37 are similarly not obvious in view of Bekkat-Berkani, Robertson, NCT03282240, NCT03698279, Chung, and/or NCT00112112. Applicant notes for the record that Applicant does not necessarily agree with the Examiner's comments about claim construction on pages 10-11 of the Action.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive as discussed supra. Bekkat-Berkani, Robertson, NCT03282240, NCT03698279 and Chung has been discussed above and NCT00112112 discloses the use of Flu Mist vaccine in immunocompromised children ages 5 through 17 years of age with cancer as required in instant claim 37 (entire trial). NCT00112112 also teaches several outcome measures including the presence of a respiratory illness, including otitis media (outcome measures), (instant claim 21). 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). Last and for the record, Applicant has not provided any reason for the disagreement regarding the Examiner's comments about claim construction on pages 10-11 of the Action.
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
/Michael Allen/ Supervisory Patent Examiner, Art Unit 1671