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 .
Status of the Application
Receipt is acknowledged of Applicants’ remarks and amendments, filed on 07/01/2026, in which claims 1, 11, and 30-31 are amended. Claims 1-31 are pending and are examined on the merits herein.
Priority
The instant application is a 371 of PCT/US2020/036685, filed on 06/08/2020, which claims domestic benefit to 62/858,034, filed on 06/06/2019.
The following are maintained or modified grounds of rejection necessitated by Applicant’s amendment, in which claims 1 and 11 are amended to recite “wherein the composition provides protection against a heterologous virus strain” and claims 30-31 are amended to recite “composition reduces lethality of a secondary bacterial infection, and wherein the subject is 55 years old or greater”.
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 (i.e., changing from AIA to pre-AIA ) 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, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-21 and 23-31 are rejected under 35 U.S.C. 103 as being unpatentable over Ernst et al. (WO 2014/138696 A1; IDS 01/24/2024) in view of Goff et al. (Journal of Virology, 2025; PTO-892 04/01/2026).
Ernst discloses methods of generating lipooligosaccharide/lipid A-based mimetics are provided that utilize recombinantly engineered bacteria to produce the mimetics (abstract and [0126]). Ernst discusses vaccines and teaches that effective component vaccines require the addition of adjuvants to increase their immunogenic capacities; lipid A mimetics that are TLR4 agonists show great promise for use as adjuvants in component vaccines [0007]. Adjuvants are useful because they reduce the amount of the active component required in an immunogenic composition, they may allow the use of fewer doses of the immunogenic composition because the immune response is stronger and lasts longer, and those with compromised immune systems benefit from them because their immune system requires an extra boost to provide protection [0083]. These adjuvants are used to provide protection against viruses [0011], and are formulated in a composition that includes the lipid A, as well as an antigen (claim 15 and [0024]). Ernst teaches that the antigen is an active ingredient [0099]. The antigens employed with the lipid A mimetics may be of any kind, including, among others, polypeptides and viral vectors [0091]. The lipid A mimetics are defined as compounds that are TLR4-signaling molecules causing immune responses when used as vaccine adjuvants [0057]. Ernst further discloses that the lipid A mimetics are useful for treating humans [0088] and mammals [0086], and that the administration would be intramuscular [0016], and the composition would include a carrier [0101]. Furthermore, Ernst discloses a method comprising administering to a subject a lipid A mimetic (claim 13), which is a single administration, and further states that an initial administration may be followed by booster administrations [0115]. Ernst teaches that the dosage of the vaccine will depend on the route of administration [0115], the age of the patient, severity of the disease condition, and previous therapeutic interventions, which can be readily determined by one of ordinary skill in the art [0114]. Ernst teaches that the dosage of the active ingredient may be, among others, about 10 micrograms per kg of body weight or 5 milligrams per kg of body weight [0115]. Ernst further provides specific examples in which candidate molecules are tested in an in vivo murine model in which animals are dosed intraperitoneally with 50 µg of candidate LOS (lipooligosaccharide) along with the antigen [0141].
Ernst teaches that protection from infectious agents known to be major causes of death, such as influenza, require vaccines, which require the addition of adjuvants such as lipid A mimics to increase their immunogenic capacities [0007], and that the composition is given to a patient as part of routine preventative measures [0085].
Ernst discloses a method of enhancing an immune response in a subject, comprising administering to the subject an effective amount of an immunogenic compound of the following general formula (claim 13).
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R1 and R2 may be selected from a Markush including protonated phosphate. R3 may be selected from a Markush including OH. R4, R5, R6, and R7 may be an alkyl or alkenyl chain of up to 13 carbons, and R8, R9, R10, and R11 may be H, OH, or an alkyl or alkenyl ester of up to 16 carbons.
Ernst specifically discloses structure B shown below (figures 1 and 13 and first compound on page 77 in claim 12).
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Structure B is identified as ∆phoP-pagP+, which is the hexa-acylated lipid A (figure 1, table 1, and [0132]), and is a representative Yp-based lipid A structure generated using BECC [0038]. This compound induces secreted RANTES cytokines at a 4-log lower dose than the positive control MPL (figures 2 and 5), which is used clinically and obtained from major manufactures [0135]. Ernst discloses that an in vitro study of this compound highlights its usefulness for further in vivo work [0135 and 0145]. Ernst indicates that in vivo work includes the administration of the lipid A in combination with an immunogen to a subject (example 5, especially [0146] and figure 6).
Ernst further teaches other lipid A mimetics, including the second structure on each of pages 77, 78, 80, and 82, in which R9 is a 16 carbon alkenyl ester designated as a 16:1 alkenyl ester. Ernst further teaches construction of additional rationally-designed LOS/lipid A structures with modified lipid A structures using BECC [0131] and provides additional lipid A modifications to design new lipid A mimics, such as altering the fatty acid content or number [0018]. This particularly includes lipid A-based mimetics having a modified fatty acid content or number compared to the endogenous bacterial lipid A molecule or a reference lipid A molecule [0022]. Ernst teaches that the level of fatty acid content may be altered through the addition or deletion of acyltransferases and/or deacylases [0131].
The teachings of Ernst differ from that of the instantly claimed invention in that Ernst does not teach wherein the viral immunogen is from an influenza virus.
Goff discloses TLR4 and TLR7 ligands as influenza virus vaccine adjuvants. Goff teaches that viruses remain a substantial public health burden, with seasonal epidemics resulting in significant morbidity, mortality, and economic loss (page 3221, paragraph 1). Goff teaches that seasonal influenza virus vaccines currently administered in the United States do not contain an adjuvant. Adjuvants spare antigen, enhance vaccine immunogenicity, direct the quality of the immune response, and may also increase the protective breadth of vaccines (page 3222, paragraph 1). Goff discloses the vaccine adjuvants 1Z105 and 1V270, and teaches that these are TLR4 and TLR7 ligands (page 3222, paragraph 1). Goff teaches recombinant hemagglutinin (rHA) antigens derived from influenza viruses including, among others, A/California/04/2009 (Cal/09) (paragraph bridging pages 3222-3223). The rHA was administered at 5, 1, or 0.2 µg/animal with or without adjuvant (Figure 5). Geoff teaches that the vaccine adjuvants have antigen sparing properties (paragraph bridging pages 3227-3228). The combination of 1Z105 or 1V270 with a recombinant HA induces rapid, long-lasting, and balanced Th1- and Th2-type immunity (abstract).
It would have been prima facie obvious before the effective filing date of the claimed invention to alter the lipid A mimic structure B in the method suggested by Ernst by altering the fatty acid content and number to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to substitute the hydroxy group on structure B with an R9 which is a 16 carbon alkenyl ester designated as a 16:1 alkenyl ester because Ernst teaches that a next step in designing new lipid A mimics is to change the fatty acid content or number of a previously reported BECC-derived molecule. One of ordinary skill in the art would have a reasonable expectation of success because Ernst teaches that compounds of the general formula are lipid A mimics and discloses additional examples of lipid A mimics in which R9 which is a 16 carbon alkenyl ester designated as a 16:1 alkenyl ester. This corresponds to the lipid A mimetic BECC438 of the instantly claimed invention.
Although Ernst does not expressly disclose administering to a subject the combination of a viral immunogen and a compound of the instant claims to a subject, it would have been prima facie obvious before the effective filing date of the claimed invention to administer a combination of a viral immunogen and 50 µg of lipid A mimic to a subject to arrive at the instantly claimed invention because Ernst teaches lipid A mimics that are useful for in vivo administration as a vaccine adjuvant which entails combined administration with an immunogen and teaches administration of 50 µg of candidate lipid A mimics. It would have been prima facie obvious for one of ordinary skill in the art to select a viral immunogen because Ernst teaches a method to provide protection against viruses and includes viral vectors as the immunogen. One of ordinary skill in the art would have a reasonable expectation of success in administering the compounds of the instant claims because Ernst teaches that compounds of the general formula are lipid A mimics.
It would have been prima facie obvious to combine the teachings of Goff and Ernst before the effective filing date of the claimed invention by including the particular antigens of Goff – including 0.2 µg of the Cal/09 rHA antigen – in the vaccines of Ernst to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to select the antigens of Goff in the lipid A containing compositions of Ernst because Ernst teaches administration of a vaccine comprising viral antigens and lipid A mimics that are TLR4 agonists, and Goff teaches viral antigens that would be administered with an adjuvant that is a TLR4 agonist. One of ordinary skill in the art would have a reasonable expectation of success because Ernst teaches that the antigens that may be employed with the lipid A mimetics may be of any kind.
Regarding the limitations “wherein the composition provides protection against a heterologous virus strain” in claims 1 and 11 and “wherein the composition reduces lethality of a secondary bacterial infection, and wherein the subject is 55 years old or greater” in instant claims 30-31, the instant specification indicates that mice that had been previously infected with influenza virus have severe responses to the secondary Streptococcus pneumoniae strain SP3 infection (page 82, lines 23-31 and Figure 10), and that a combination of 0.04 µg HA and 50 µg BECC438 or BECC470 provided protection from homologous challenge with influenza NL/09 in elderly mice (figures 53-61). The instant specification indicates that administration of 5 µg, 1 µg, and 0.2 µg hemagglutinin confers protection (Figure 7 and page 81, lines 25-27). Furthermore, the instant specification indicates that administration of an adjuvanted vaccine comprising 0.04 µg hemagglutinin and 50 µg BECC438 to mice provides protection from heterologous challenge (Example 1, starting on page 64, especially paragraph bridging pages 67-68). Although the combined teachings of Ernst and Goff do not teach that the administration of BECC438 as compared to a control provides protection against a heterologous virus strain or reduces lethality of a secondary bacterial infection in a subject older than 55 years, the combined teachings of the prior art teach and suggest administration of a composition comprising 0.2 ug of the Cal/09 rHA and 50 µg of a lipid A mimetic of the same structure as BECC438, which would provide a vaccine of the same chemical composition as that of the instantly claimed method, and thereby necessarily result in the same properties of immune response. MPEP 2112.01(II) states that products of identical chemical composition cannot have mutually exclusive properties. Furthermore, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. MPEP 2112(I) states that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer."
Similarly, regarding the limitation “the immune response has a Thl/Th2 profile that is more balanced as compared to an immune response elicited by phosphorylated hexa-acyl disaccharide” in instant claim 3 and 12, “the composition induces greater IgG production as compared to a composition lacking the adjuvant” in instant claim 6 and 16, and “the composition causes less inflammation as compared to a composition lacking the adjuvant” in instant claim 7 and 17, the instant specification (Example 1, starting on page 64) indicates that the effect of administration of 0.04 µg of Cal/09 rHA and 50 µg of BECC438 to mice as compared to administration of a control HA only elicits a balanced TH1/Th2-type immune response (page 66, line 6-7), has greatly increased IgG antibody titers (page 65, line 20), and has lowered inflammation (page 66, line 5 and Figure 12I). Although the combined teachings of Ernst and Goff do not teach that the administration of Cal/09 rHA and BECC438 as compared to a control of HA only provides an immune response has a Thl/Th2 profile that is more balanced, induces greater IgG production, and causes less inflammation, the combined teachings of the prior art teach and suggest the instantly claimed composition, which would provide a vaccine of the same chemical composition as that of the instantly claimed method, and thereby necessarily result in the same properties of immune response, IgG production, and lowered inflammation level.
Regarding instant claim 29, Ernst does not disclose that the subject is 55 years or greater (instant claim 29). It would have been prima facie obvious before the effective filing date of the claimed invention to select a patient of any age, thereby arriving at the instantly claimed invention, because Ernst teaches that the dosage of the composition can be adjusted to suit the age of the patient. Furthermore, a patient at any age is in need of routine preventative measures for protection from infectious agents known to be major causes of death. One of ordinary skill in the art would have a reasonable expectation of success in selecting the dosage of the viral immunogen because Ernst teaches that this can readily be determined by one of ordinary skill in the art.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Ernst et al. (WO 2014/138696 A1; IDS 01/24/2024) in view of Goff et al. (Journal of Virology, 2025; PTO-892 04/01/2026) as applied to claim 11 above, further in view of Morris et al. (Frontiers in Microbiology, 2017; PTO-892 04/07/2025).
The combined teachings of Ernst and Goff are as above. Furthermore, Ernst teaches that the compositions confer protection against lethal bacterial infection [0156]. Ernst teaches that the taught lipid A mimetic is employed for immune stimulation for a pathogen, such as any bacteria or virus, including Haemophilus influenzae type B and pneumonia [0086]. In addition, protection from infectious agents known to be major causes of death, such as influenza, require vaccines, which require the addition of adjuvants such as lipid A mimics to increase their immunogenic capacities [0007].
The combined teachings of Ernst and Goff differ from that of the instantly claimed invention in that they do not teach that the method reduces lethality of a secondary bacterial infection (instant claim 22).
Morris teaches that a common complication of respiratory viral disease is secondary bacterial infection (page 2, paragraph 1). Secondary bacterial infection frequently occurs in infection by influenza virus and can significantly increase the morbidity and mortality of viral infections (page 3, paragraph 3). H. influenzae commonly co-infects with influenza virus synergistically, resulting in more severe morbidity (page 6, paragraph 3). Morris teaches that the effect of viral prevention methods further supports the idea of viruses predisposing a host to secondary bacterial infection. Furthermore, studies have shown that influenza vaccination can reduce the occurrence of bacterial pneumonia (page 10, paragraph 4).
It would have been prima facie obvious to administer the influenza vaccine comprising a lipid A mimic suggested by Ernst and Goff to reduce the lethality of the secondary bacterial infection described by Morris, thereby arriving at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to reduce the lethality of a secondary bacterial infection by administering the composition comprising a lipid A mimic because Ernst suggests that the lipid A compositions are both useful for influenza viral vaccinations and provides immune stimulation against Haemophilus influenzae, and Morris teaches that H. influenzae commonly co-infects with influenza, indicating that protection against H. influenzae would provide protection against the common secondary bacterial infection.
Response to Arguments
Applicant's arguments filed 07/01/2026 have been fully considered but they are not persuasive.
Applicant argues that because the claims are rejected under grounds of obviousness, rather than anticipation, any inherent anticipation rationales or other rationales related to properties assumed to be in the prior art, such as those of the MPEP section cited in the nonfinal rejection, are not applicable (Remarks, page 12, paragraph 1). This is not persuasive.
As discussed in the modified grounds of rejection above, the combined teachings of Ernst and Goff render obvious the administration of a composition comprising the same compounds in the same amounts, which include the same effective amount of 50 µg of the same lipid A mimic and 0.2 µg of the same hemagglutinin protein, to the same patient populations, which include any patient in need of protection from viral infection, which thereby includes patients of any age, and thereby necessarily result in the same properties of immune response. MPEP 2112.IV states that: "[I]n order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis – the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art." The claimed effect of the instantly claimed compositions is thus a natural result of the combination of elements which have been explicitly disclosed by the teachings of Ernst and Goff.
Applicant further argues that the claims have been amended to recite that the composition provides protection against a heterologous virus strain as shown in Figures 50-52 and 65-66, and that lack of protection against heterologous challenge for influenza is a known long-standing problem that has eluded a solution, and a person having ordinary skill would not have been able to predict which specific compositions would provide such a protection (Remarks, page 13, paragraph 2). This is not persuasive.
Applicant's arguments amount to an argument from long felt need. In order to establish long-felt need, Applicant must establish that the need has been a persistent one that was recognized by those of ordinary skill in the art. MPEP 716.04 states that an argument of long-felt need and failure of others must satisfy a long-felt need which was recognized, persistent, and not solved by others. However, Applicant has failed to demonstrate that protection against heterologous challenge for influenza was recognized by those of ordinary skill in the art as a persistent need. Goff teaches that seasonal influenza virus vaccines are currently administered in the United States (page 3222, paragraph 1). Applicant has not established that a protection against heterologous challenge for influenza was recognized in the art as being necessary, as other vaccines were available for protection against influenza virus. Thus, Applicant has not submitted evidence to satisfy the requirement of a long-felt need.
Applicant further argues that the results obtained with elderly mice as shown in Figures 55-61 are particularly surprising, and would not have been predictable to a person having ordinary skill in the art. Applicant argues that the claimed compositions are effective in hard-to-vaccinate groups, such as those over the age of 55, and such results are unexpected and not suggested by the cited art (Remarks, page 13, paragraph 2). This is not persuasive.
Applicant's arguments amount to an argument from unexpected results. In order to demonstrate unexpected results for the claimed compositions, Applicant must provide a comparison showing a statistically significant difference between the claimed invention for the administration to hard to vaccinate groups versus that of the teachings of the prior art in Ernst, which do not teach administration to patients over the age of 55 and is silent regarding administration to aged subjects. The data of Figures 55-61 provides results of vaccination with 0.04 µg HA plus 50 µg of the adjuvant BECC470 or BECC 438. However, the instant specification does not provide a comparison the treatment of patients over the age of 55 versus that of patients who are not of the hard to vaccinate group. Thus the argument is not persuasive.
Because Applicant’s arguments are not persuasive, the instant claims are rejected for reasons of record.
Conclusion
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 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 date of this final action.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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