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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/05/2026 has been entered.
Status of the Application
Receipt is acknowledged of Applicants’ preliminary amendment, filed on 02/05/2026, in which claims 1, 3, 6-7, 11-12, and 16-17 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.
Objections and Rejections Withdrawn
Applicant’s amendment and remarks, filed 02/05/2026, with respect that the drawings are objected to, has been fully considered and is persuasive, as replacement drawings and a petition for color drawings have been filed. This objection has been withdrawn.
Applicant’s amendment and remarks, filed 02/05/2026, with respect that claims 1-2, 8, 10-13, 18, 20-21, 23-25, and 28-31 are rejected under 35 U.S.C. 103 as being unpatentable over Ernst has been fully considered and is withdrawn in favor of the new rejection below. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 02/05/2026, with respect that claims 3-7, 9, 14-17, 19, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Ernst in view of Jiang has been fully considered and is withdrawn in favor of the new rejection below. This rejection has been withdrawn.
Applicant’s amendment and remarks, filed 02/05/2026, with respect that claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Ernst in view of Morris has been fully considered and is withdrawn in favor of the new rejection below. This rejection has been withdrawn.
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).
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 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 (H1N1) (Cal/09) (paragraph bridging pages 3222-3223). 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 lipid A mimic to a subject to arrive at the instantly claimed invention because Ernst teaches lipid A mimics useful for in vivo administration as a vaccine adjuvant which entails combined administration with an immunogen. 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 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 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 Cal/09 rHA and 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. 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."
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 55 years or greater to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to select a patient of greater than 55 years 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 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 02/05/2026 have been fully considered but they are not persuasive. Insofar as Applicant’s arguments are applicable to the current rejections, Applicant argues that ∆phoP-pagP+ is a speculative lead compound, the set of modifications to be considered is not practically finite, and because each modification or group of modifications would require extensive experimentation to engineer groups of enzymes corresponding to a particular bacterial strain, to develop machinery and to verify the properties of the produced/isolated compounds (paragraph bridging pages 18-19). This is not persuasive.
As discussed in the above grounds of rejection, 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. Ernst teaches that ∆phoP-pagP+ is a representative Yp-based lipid A structure generated using BECC. ∆phoP-pagP+ induces secreted RANTES cytokines at a 4-log lower dose than the positive control MPL, which is used clinically. Thus, rather than being a speculative lead compound, ∆phoP-pagP+ is suggested as a lead compound by Ernst. Regarding Applicant’s argument that the set of modifications to be considered is not practically finite, Ernst teaches that a next step is modifying fatty acid content or number compared to the reference lipid A molecule, and teaches other lipid A mimetics in which R9 is a 16:1 alkenyl ester. Thus Ernst specifically teaches the particular modification to reach the instantly claimed compound. Regarding Applicant’s argument that each modification would require extensive experimentation to engineer groups of enzymes corresponding to a particular bacterial strain, to develop machinery, and to verify the properties of the produced/isolated compounds, Ernst teaches BECC as a general strategy for construction of additional rationally-designed LOS/lipid A structures, specifically teaches that the level of fatty acid content may be altered through the addition or deletion of acyltransferases and/or deacylases, and provides experimental direction such that achieving a method of synthesizing this suggested compound is routine and conventional in view of the teachings of Ernst.
Similarly, Applicant argues that the express teachings available to the person of ordinary skill in the art relating to structure/function interaction of lipid A mimetics and the host innate immune receptor (TLR4) are not detailed enough to lead a researcher directly to Applicant's claimed compounds because Ernst provides a broad generic structure (page 22, paragraph 1). This is not persuasive.
As discussed above, Ernst goes beyond providing a generic structure in teaching specific types of modifications to be made, including altering the fatty acid content or number, especially compared to a reference lipid A molecule, and provides ∆phoP-pagP+ is a representative lipid A structure.
Applicant further argues that a person of ordinary skill in the art would not have been able to predict the properties of a resulting vaccine merely from modifications made to the structures of the adjuvant compounds (paragraph bridging pages 19-20), specifically the beneficial properties of Applicant's claimed compounds including balanced Thl/Th2 profile compared to PHAD, high IgG titer and low inflammation (page 21, paragraph 2). This is not persuasive.
As discussed in the above grounds of rejection, 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." Furthermore, Applicant has not provided a demonstration of unexpected results by providing a comparison to the closest prior art in Ernst. MPEP 716.02(b) states that the evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and are of both statistical and practical significance.
Conclusion
No claims are allowed.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693