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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is drawn from PCT/US2022/012801, filed 1/18/2022; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 63/138163, filed 1/15/2021.
Status of Claims
Claims 1-7, 9-11, 13, 15, 17-19, 21-22 and 25-27 are pending and are being examined on the merits.
Claim Objections
Claim 5 is objected to because of the following informalities: Claim 5 recites the “composition comprises adjuvant and a antigenic material”. This phrase is missing an identifier before “adjuvant”, (i.e. “an”); and the identifier before “antigenic material” should be “an”, and not “a”, as antigenic begins with a vowel. The phrase should read as the “composition comprises an adjuvant and an antigenic material”. Appropriate correction is required.
Claim 11 is objected to because of the following informalities: Claim 11 recites “such as TNF, IL-6, IL-1 beta.”. There should be a conjunction (i.e., “and” or “or”) coordinating the grouping of alternative species as combined (i.e., and) or as alternatives (i.e., or). Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 7, 9-11, 15, 18-19, 21-22 and 26-27 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 7, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is unclear if AS03 and/or MF59 are intended to be the claimed invention or the invention encompasses the breadth of any emulsion comprising squalene. As the metes and bounds of the claim limitations are unclear, claim 7 is rejected for indefiniteness. Examiner suggests applicants remove “optional” language if such language is not intended to limit the scope of the claims.
Regarding claim 9, the phrase “including” is interpreted as equivalent to "such as", and thus renders the claim indefinite because it is unclear whether the limitations following the phrase are required. See MPEP § 2173.05(d). It is unclear if the TLR ligand is required to be specific for TLR7/8, TLR3 or TLR4, or the invention encompasses any TLR ligand. Thus the metes and bounds of the claim are unclear, and claim 9 is rejected for indefiniteness.
Claim 10 recites “wherein the adjuvant is encapsulated in a nanoparticle or in other formulations.” It is unclear if the claim requires “encapsulation”, either in a nanoparticle or in other formulations, or if the adjuvant may be “formulated”, either in an encapsulated in a nanoparticle or otherwise formulated in other formulations. The specifications do not mention “encapsulate”, “encapsulated” or “encapsulation”, and thus do not provide any further definition regarding the scope of encapsulation. The specifications do describe a SARS-CoV-2 Spike protein receptor binding domain displayed on a two-component protein nanoparticle (pg. 59, para. 00194), and thus teach an antigen in a nanoparticle; however, the antigen/nanoparticle was “formulated” with various adjuvants, resulting in “adjuvating a subunit SARS-CoV-2 nanoparticle vaccine”, (pg. 59, para. 00194). Thus, the specifications do not describe the process of encapsulating an adjuvant in a nanoparticle, or whether encapsulated nanoparticles are encompassed in the scope of formulations. Therefore it is unclear what the limitations of the formulation are, or whether the formulations require encapsulation in a nanoparticle. As the metes and bounds of the claim are unclear, claim 10 is rejected for indefiniteness.
Regarding claim 11, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is unclear if the cytokines that are refractory to being produced are limited to TNF, IL-6 and/or IL-1 beta, or whether any cytokines that are refractory to being produced meet the limitation of the claims. Further, the cytokine alternatives listed “TNF, IL-6, IL-1 beta” do not have a conjunction connecting the alternatives. Thus, it is unclear if the claim requires TNF, IL-6 and IL-1 beta to all be refractory to being produced, or if the lack of production of any one of TNF, IL-6 or IL-1 beta is sufficient to meet the claim limitation. As the metes and bounds of the claim limitations are unclear, claim 11 is rejected for indefiniteness.
Regarding claim 15, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is unclear if the claim requires that the administration occurs before an individual would be at increased risk of pathogen exposure, or if administering the composition as a prophylactic for a viral infection, at any time, meets the claim limitation. As the metes and bounds of the claim limitations are unclear, claim 15 is rejected for indefiniteness. Examiner suggests applicants remove “optional” language if such language is not intended to limit the scope of the claims.
Claim 18 recites “wherein administration is repeated at ‘suitable’ intervals as the immune responsive state ‘fades’”. The claim is drawn to a protocol for administering or dosing the individual repeatedly. The “immune responsive state” requires parameter(s) which define the state, such that the parameters can objectively indicate when the state “fades” to a sufficient degree to meet the threshold wherein it is “suitable” for re-administration of the composition. There is insufficient antecedent basis for the parameters of “immune responsive state” in claim 18; such parameters are first described in claim 21. The specifications recite the terms “suitable” and “fades” only once (pg. 2, para. 0008), and do not provide any parameters which would define these terms with regard to the immune responsive state. Without the parameters that define these vague terms, the metes and bounds of the claim are unclear, and the skilled artisan does not know when they are infringing on the claim. The parameter defining the immune responsive state, the changes in degree of said parameter which define sufficient “fading”, and at what interval a re-administration would be “suitable” should be defined, and not subjective. As the metes and bounds of the claim limitations are unclear, claim 18 is rejected for indefiniteness. Examiner suggests applicants amend the claim to remove the terms “suitable” and “fades”, such that the claim depends from the method of claim 1, and whereby the method comprises repeated (or “more than one”) administrations of the composition as required. See specifications, pg. 28, para. 00111; first sentence.
Regarding claim 19, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is unclear if the claim is limited to classical monocytes and myeloid dendritic cells or encompasses any myeloid cell type. As the metes and bounds of the claim limitations are unclear, claim 19 is rejected for indefiniteness. Examiner suggests applicants remove “optional” language if such language is not intended to limit the scope of the claims.
Claim 21 recites the limitation "a responsive state" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 21 depends from claim 19, which depends from claim 1. Claim 1 broadly encompasses a method for modulating the epigenome of innate immune cells, but does not recite eliciting “a responsive state”. Claim 19 recites wherein the individual is monitored for “epigenetic changes” in myeloid cells, but also does not recite eliciting “a responsive state”. Claim 21 defines what limitations characterize a responsive state, but there is not antecedent basis for a responsive state of the method. It is unclear if the “responsive state” is intended to be an equivalent to the “epigenetic changes” of claim 19. That is, while claim 21 characterizes a responsive state, claims 1 and 19 do not recite a method of eliciting a responsive state, rather they are drawn to “epigenetic changes”.
Regarding claim 22, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is unclear if the epigenetic monitoring limitation of the claim requires the specific single cell techniques that are recited after the term “optionally” (for example, as recited in claim 25), or if any single cell technique can be used to accomplish epigenetic monitoring. As the metes and bounds of the claim limitations are unclear, claim 22 is rejected for indefiniteness. Examiner suggests applicants remove “optional” language if such language is not intended to limit the scope of the claims.
Claim 26 recites an “epigenetic signature” in monocytes is characterized by enhanced chromatin accessibility of the IRf1, IRf2, STAT1, STAT2, IRF7, IRF8, STAT5b, USF1 loci, and is used as a biomarker. However, there is no conjugate to the grouping of different loci. Does the “epigenetic signature” that is used as a biomarker require that all the IRf1, IRf2, STAT1, STAT2, IRF7, IRF8, STAT5b and USF1 loci have enhanced chromatin accessibility, or that any one of the IRf1, IRf2, STAT1, STAT2, IRF7, IRF8, STAT5b or USF1 loci have enhanced chromatin accessibility? As the claim recites the “epigenetic signature” is used as a biomarker for predicting susceptibility or resistance to viral infection, the precise definition of the corresponding “signature” is required. Further, the claim recites the epigenetic signature in “monocytes and mDCs or other cells”. This is confusing grammar. Does the claim require the signature in monocytes and mDCs, or monocytes and other cells, or any one of monocytes or mDCs or other cells? As the required parameters of the “epigenetic signature” are unclear, and the subset(s) of cells that are to be measured for the epigenetic signature are unclear, the metes and bounds of the claim are unclear, and claim 26 is rejected for indefiniteness.
Claim 27 recites an “epigenetic signature” in monocytes is characterized by reduced chromatin accessibility of the AP-1, Jun, Fos loci, is used as a biomarker. However, there is no conjugate to the grouping of different loci. Does the “epigenetic signature” that is used as a biomarker require that all of the AP-1, Jun and Fos loci have enhanced chromatin accessibility, or that any one of the AP-1, Jun or Fos loci have enhanced chromatin accessibility? Further, the claim recites the epigenetic signature in “monocytes and mDCs or other cells”. Does the claim require the signature in monocytes and mDCs, or monocytes and other cells, or any one of monocytes or mDCs or other cells? As the claim recites the “epigenetic signature” is used as a biomarker for predicting susceptibility or enhanced inflammation or sepsis in viral or bacterial infection, the precise definition of the corresponding “epigenetic signature” is required. As the required parameters of the “epigenetic signature” are unclear, and the subset(s) of cells that are to be measured for the epigenetic signature are unclear, the metes and bounds of the claim are also unclear, and claim 27 is rejected for indefiniteness.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 13 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 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. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 13 recites the method in claim 12; however, claim 12 has been canceled. Therefore it is unclear what limitations, regarding the methods of the claim(s) from which claim 13 depends, are to be incorporated in claim 13. Thus, claim 13 is indefinite.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claim 11 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice... reduction to drawings...or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claim 11 recites the method of administering an adjuvant of claim 1, wherein the adjuvant stimulates an epigenetic state in monocytes, mDCs or myeloid cells that imprints enhanced antiviral resistance, and/or makes them refractory to producing pro-inflammatory cytokines such as TNF, IL-6 (and/or) IL-1 beta. The broadest reasonable interpretation of claim 11 is to a method of administering any adjuvant, and are thus drawn to a genus of adjuvants for use in the claimed method.
In support of the claimed genus of adjuvants, the specifications disclose numerous candidate agents. Specifically, “a candidate adjuvant is screened for efficacy in enhancing immune responsiveness, by administering the candidate adjuvant to an individual or an animal model, and determining the effect on the epigenetic state of myeloid cells. An adjuvant suitable for the purposes described herein can induce a responsiveness state in relevant myeloid cells, and may be selected for administration,” (specs. pg. 29, para. 00115). Further, “candidate agents of interest are biologically active agents that encompass numerous chemical classes, primarily organic molecules,” and also include “compounds, obtained from a wide variety of sources including libraries of synthetic or natural compounds,” (pg. 29, para. 00116). Thus, applicants describe the adjuvants of the invention may be selected from a vast number of natural agents, synthetic compounds or combinatorial libraries of agents with chemical modifications. The only guidance as to which agents are suitable for use in the methods being to “administer the agents and screen for biological activity in a plurality of cells, e.g. myeloid cells,” (pg. 29, para. 00117). Applicants describe adjuvants of interest include those approved for clinical use, including aluminum, AS04, MF59, AS01b and CpG 1018 (pg. 20, para. 0085); as well as Toll-like receptor (TLR) agonists (pg. 21, para. 0086). Thus, the specifications describe a vast number of candidate agents, within the claimed genus of adjuvants, which may be useful as adjuvants in the methods.
Regarding the required “epigenetic state” of claim 11, the specifications describe “the capacity of an individual to respond to pathogen challenge is highly correlated with the epigenetic state of myeloid cells; however this state is not static, but rather can be profoundly influenced by prior immune responses,” (pg. 3, para. 0010). Further, “that epigenetic changes that enhance innate immunity can be characterized by increased chromatin accessibility at interferon regulatory factor (IRF) loci, enhanced antiviral gene expression, and elevated interferon production. In addition, monocytes and mDC exhibit a state of immune refractoriness (as judged by reduced production of inflammatory cytokines), which state of refractoriness is characterized by reduced histone acetylation and decreased chromatin accessibility at AP-1 loci,” (pg. 3, para. 0012). Thus, an “epigenetic state” is not a term known in the art for enhancing the innate immunity against pathogens. Rather, every cell has an “epigenetic state” at any point in time, and that state is not static. Regarding what epigenetic state “imprints enhanced antiviral resistance”, the specifications describe “TIV-induced epigenomic reprogramming is imprinted during the acute phase of the vaccine response; on the gene level, we observed a reduction in the expression of multiple AP-1 members including ATF3, JUND, JUINB, FOS and FOSL2,” (pg. 38, para. 00141). However, that example was not using an adjuvant alone, rather it was trivalent inactivated seasonal influenza vaccine (TIV), to identify markers of the ability of TIV to reduce Ap-1 accessibility for prolonged durations, and therefore included the effects of TIV antigen on innate immune cell epigenetic modulation.
The specifications do not define the parameters of the “epigenetic state” that is necessary to “imprint enhanced antiviral resistance and/or make them refractory to production pro-inflammatory cytokines”. Further, applicants suggest a vast number of candidate agents, with no teaching of the structure/function relationship, or what structural features, which must be common to all species of the claimed adjuvants, are necessary to impart the desired functional properties. The only teachings of which adjuvants would work in the claimed invention are to screen the candidate agents and determine if changes in chromatin accessibility at IRF loci or changes in AP-1 accessibility have occurred. Applicants are reminded that the written description requirement is separate and distinct from the enablement requirement (MPEP Section 2161(II)). Thus, while teachings of methods of screening various candidate adjuvants for functionality might enable an artisan to make the invention, such screening methods do not describe the adjuvants, which applicants are in possession of, for use in the claimed methods, or the structural commonalities of all adjuvant species which would impart the desired functional properties on the epigenetic state. This is akin to claiming all antibodies which bind to epitope X, without providing any examples of such antibodies or describing the necessary structural binding domains of the antibody that impart its desired functional binding properties; thus leaving it to the skilled artisan to “discover” which antibody species actually bind the target epitope.
Regarding working examples, the applicants used AS03-adjuvanted H5N1, in Example 1 (pg. 31, para. 00122), to demonstrate that influenza vaccines stimulate persistent epigenomic remodeling of the innate immune system. In Example 2 (pg. 59, para. 00194), applicants evaluated five different adjuvants, combined with the SARS-CoV-2 spike protein receptor binding domain displayed in a two-component protein nanoparticle (RBD-NP) to stimulate neutralizing antibody responses. The five adjuvants are Essai O/W 1849101, AS03, AS37, CpG 1018-Alum, or Alum. Of those, all but O/W induced detectable nAB responses against SARS-CoV-2 virus (pg. 61, para. 00198). However, in Example 2, no screening of the epigenetic state of the myeloid cells was presented. Further, in both Examples, the adjuvants were combined with a viral antigen, in a vaccine composition. Thus, there are no representative examples of an adjuvant that, when administered alone, produces the “epigenetic state” that “imprints enhanced antiviral resistance.”
Section 2163(II)(A)(3)(a)(ii) of the MPEP states that the written description for a claimed genus may be satisfied through either a) a representative number of species, or b) disclosed correlation between function and structure. Here the applicants do not provide any species of the claimed genus of adjuvants, which were reduced to practice to demonstrate which adjuvants modulate the epigenome of innate immune cells so as to stimulate an “epigenetic state” that imprints enhanced antiviral resistance. Further, applicants do not identify the shared structural properties of the adjuvant species which would define the genus beyond the desired functionality. Specifically, the physical features of the adjuvants which impart the epigenetic state properties of increased chromatin accessibility at interferon regulatory factor (IRF) loci, enhanced antiviral gene expression, and elevated interferon production, and/or reduced AP-1 accessibility, should be described. The structural properties that impart the desired function would be essential in determining the degree to which any adjuvant, or candidate agent, may be allotted for use in the claimed method. This lack of definition complicates the determination of the boundaries of the claimed genus with regard to which, as of yet unscreened, adjuvant candidate agents would be anticipated, a priori, by one skilled in the art, to fall within the scope of the claims. Without the identification of the necessary shared structural properties of all species variants that fall within the scope of the genus, it is left to the artisan to perform the screening experiments in order to identify which adjuvants, among a vast number of alternatives, may be used in the invention, or infringe on the claimed methods.
“The purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04. Otherwise, the “claims merely recite a description of the problem to be solved while claiming all solutions to it and … cover any compound later actually invented and determined to fall within the claim’s functional boundaries- leaving it to the pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1353 (Fed. Cir. 2010).
In view of the uncertainty regarding the parameters of the required “epigenetic state”, the lack of description of the structure/function relationship between candidate adjuvants and the desired modulation of the epigenome, and the lack of a representative number of examples of the claimed genus, claim 11 is rejected for lack of adequate written description support.
Claim Rejections - 35 USC § 112(a)
Claim 10 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 10 recites “wherein the adjuvant is encapsulated in a nanoparticle or in other formulations.” The specifications do not describe any adjuvant being encapsulated in a nanoparticle. The specifications do not mention “encapsulate”, “encapsulated” or “encapsulation”, and thus do not provide any further definition regarding the scope of encapsulation. For example, would a viral vector comprising a nucleotide encoding the adjuvant meet the definition of encapsulated? Regarding wherein the adjuvant is encapsulated in a nanoparticle, the specifications describe a SARS-CoV-2 Spike protein receptor binding domain displayed on a two-component protein nanoparticle (pg. 59, para. 00194), and thus teach an antigen in a nanoparticle. However, the antigen/nanoparticle was “formulated” with various adjuvants, resulting in “adjuvating a subunit SARS-CoV-2 nanoparticle vaccine”, (pg. 59, para. 00194). That is the only description of a nanoparticle in the specifications. Thus, the specifications do not describe the process of encapsulating an adjuvant in a nanoparticle, or which processes of encapsulated nanoparticles are encompassed in the scope of formulations. For example, Levy et al. (from IDS; US 20200282048) describes vaccine compositions formulated in a nanoparticle, specifically, a lipid nanoparticle (LPN; pg. 44, para. 0223). Levy goes on to describe the various lipids, ratios and compositions for generating a vaccine formulated in a lipid nanoparticle (pg. 45, full). No such description, or even suggestion, of formulating the adjuvant of the instant claims in lipid nanoparticles is described in the instant specifications. Thus, claim 10 is rejected for introduction of new matter, with a lack of descriptive support for conception or possession of the new matter as claimed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-7, 11, 15 and 17-18 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Rothman et al., (from IDS of 7/5/2023; US 9,463,227; issued 10/11/2016).
Rothman et al. teaches methods of providing an adjuvant for enhancing immune responses in a subject (abstract). Rothman teaches listeria monocytogenes and a protein named listeriolysin O (LLO) have strong adjuvant properties (col. 1, lines 33-35). Rothman teaches that administering Listeria vaccine strain can reconstitute the immune response or facilitate the recovery of an immune response in subjects that have undergone cytotoxic treatment as a result of cancer (col. 1, lines 47-50); can improve the immunogenicity of a vaccine when co-administered (col. 2, lines 11-12); or can enhance an immune response against a disease in an antigen-independent manner (col. 2, lines 18-20). Rothman teaches the Listeria vaccine strain is devoid of exogenous antigen (col. 5, lines 4-5). Rothman teaches the invention is for preventing disease, treating disease or vaccinating a human subject, or to enhance the immune response of a human (col. 6, lines 28-32). Rothman teaches the immune response elicited comprises an innate immune response wherein M1 macrophages and dendritic cells (DC) are activated (col. 25, lines 18-21). Rothman teaches “a poorly described property of LLO is its ability to induce epigenetic modifications affecting control of DNA expression; extracellular LLO induces a dephosphorylation of the histone protein H3 and a similar deacetylation of the histone H4.” This epigenetic effect provides a mechanism by which LLO may regulate the expression of gene products required for immune responses (col. 26, lines 44-60). Rothman teaches the present invention provides a method of eliciting an enhanced immune response to an infectious disease in a subject; in an embodiment, the immune response is not antigen specific (col. 30, lines 19-25).
Regarding claims 1, 11 and 15; Rothman teaches a method of enhancing innate immunity, comprising administering Listeria vaccine to a subject, wherein the Listeria produces LLO, which both act as an adjuvant, which epigenetically enhances the innate immune response against pathogenic diseases, and which is not antigen specific. Thus the methods of Rothman anticipate the methods of instant claim 1. Further, Rothman teaches the immune response of the methods of the invention are a prophylactic immune response (col. 8, line 40) and may be used to treat, or protect people at risk of, any infectious disease, including viral infections and influenza (col. 8, lines 47-49; see also col. 31, lines 46-49). Thus, the methods of Rothman anticipate instant claims 11 and 15.
Regarding claims 2-3, Rothman teaches a live attenuated Listeria vaccine strain devoid of antigen that enables the Listeria to secrete only the non-hemolytic form of LLO as an adjuvant; the invention provided herein addresses the first live adjuvant (col. 5, lines 7-12). Rothman teaches a method of enhancing an immune response against a disease in an antigen-independent manner (col. 9, lines 15-16); and that the Listeria-based adjuvant is used alone or is combined with another adjuvant (col. 9, lines 44-45). Thus, Rothman teaches Listeria-based adjuvant compositions that lack additional antigens (re. claim 2) or wherein the composition consists of only an adjuvant (re. claim 3). Thus, the methods of Rothman anticipate instant claims 2-3.
Regarding claims 4-5; Rothman teaches that, in one embodiment, the invention relates to a method of improving the immunogenicity of a vaccine, said method comprising the step of co-administering the vaccine and a Listeria-based adjuvant to a subject (col. 2, lines 11-14). Rothman teaches the invention provides a method of preventing the onset of an infectious disease, wherein the infectious disease is Influenza seasonal (col. 30, lines 26-27, line 44). Thus, the invention of Rothman encompasses combining the Listeria-based adjuvant with a seasonal influenza vaccine, and therefore anticipates instant claims 4-5.
Regarding claims 6-7; Rothman teaches that the adjuvant of the present invention is combined with an additional adjuvant (col. 9, lines 44-45), whereby the additional adjuvant is any adjuvant known in the art (col. 10, lines 8-9). Specifically, Rothman teaches the additional adjuvant is SBAS2 (col. 9, line 60). It is known in the art that SBAS2, aka AS02, is a water-in-oil emulsion comprising squalene. Thus, the methods of Rothman, comprising the Listeria-based adjuvant combined with SBAS2 adjuvant anticipates the water-in-oil emulsion adjuvant of instant claim 6, as well as wherein the emulsion comprises squalene of instant claim 7.
Regarding claim 17; Rothman teaches the method is provided to reconstitute the immune response or facilitate the recovery of an immune response to normal levels in subjects that have undergone cytotoxic treatment as a result of cancer (col. 1, lines 47-50). Rothman teaches the adjuvant enhances an immune response in an antigen-unspecified manner in order to enable a heightened state of an immune response as it applies to neonates, or older children and adults following cytotoxic treatment (col. 33, lines 1-5). Thus, Rothman teaches the methods are applied to subjects with reduced adaptive immune responses, and therefore anticipates instant claim 17.
Regarding claim 18, Rothman teaches experiments in which the vaccine was administered in mice which were implanted with tumors. Rothman teaches 7 days after tumor implantation the mice were vaccinated; the mice were then administered a booster vaccine one week after the vaccine was given (col. 47, lines 27-32). Thus, Rothman teaches that administration may be repeated at suitable intervals, and therefore the methods of Rothman anticipate instant claim 18.
Claim Rejections - 35 USC § 102
Claims 1-7, 9-10, 15 and 17-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Forsbach et al., (EP 1957647; published 4/3/2015).
Forsbach et al. teach oligoribonucleotides with immunostimulatory activity (title). Forsbach teaches Toll-like receptors (TLRs) play a critical role in innate immunity, (pg. 2, para. 0002). Specifically, Forsbach teaches the immunostimulatory oligoribonucleotides (ORN) of the invention are agonists for TLR8 (pg. 2, para. 0007 – pg. 3, top). Thus Forsbach teaches the ORN of the invention, as well as compositions comprising the ORN and methods of using the ORN, are useful for stimulating or augmenting an immune response (pg. 2, para. 0005); including the step of administering to a subject an effective amount of a composition of an ORN of the invention (pg. 5, para. 0033).
Regarding claims 1-3; Forsbach teaches an immunostimulatory composition including the immunostimulatory ORN of the invention and an adjuvant (pg. 4, para. 0021). Forsbach teaches the ORN composition may be administered with or without an antigen (pg. 5, para. 0033). Forsbach teaches and immune-stimulating adjuvant is an adjuvant that causes activation of cda cell of the immune system. Thus, in one aspect the invention provides an adjuvant that includes an immunostimulatory ORN of the invention, by itself. Or, in an alternative embodiment, the invention provides the ORN of the invention and at least one other adjuvant, a combination adjuvant (pg. 15, para. 0097). Thus the invention of Forsbach, comprising administering an immunostimulatory composition comprising the ORN as an adjuvant, to stimulate innate immunity against pathogens, without any additional antigens, anticipate instant claims 1-3.
Regarding claims 4-5; Forsbach teaches the ORN of the invention may be used as a vaccine, wherein the vaccine comprises the ORN, an antigen and a pharmaceutically acceptable carrier (pg. 17, paras. 0106-0107); and whereby the antigen may be a microbial antigen from a virus (paras. 0108-0109), and whereby it is derived from influenza virus (para. 0110). Thus the methods of Forsbach anticipate instant claims 4-5.
Regarding claims 6-7; Forsbach teaches the immunostimulatory ORN of the invention are useful alone or in combination with other agents, as adjuvants (pg. 15, para. 0093). Suitable adjuvants include water-in-oil emulsions, including those comprising squalene, including MF59 (pg. 15, para. 0094). Thus, the methods and compositions of Forsbach anticipate instant claims 6-7.
Regarding claim 9; Forsbach teaches the adjuvant ORN of the invention is a TLR8 agonist (pg. 2, para. 0007); thus Forsbach anticipates instant claim 9.
Regarding claim 10, Forsbach teaches a pharmaceutical composition which includes a composition of the ORN of the invention in association with a delivery vehicle. In various embodiment the delivery vehicle cha be chosen from a liposome, a microparticle or a nanosphere (pg. 19, para. 0126). Thus, Forsbach anticipates instant claim 10.
Regarding claim 15; Forsbach teaches the use in therapy of the invention may be for the purpose of immunization, i.e. prophylactic (pg. 30, para. 0226); that the word “treat” shall mean to prevent or ameliorate (pg. 21, para. 0146); including a subject having an infection, which may be a viral infection (pg. 21, para. 0147). Forsbach teaches a method of vaccinating a subject may include the composition of an ORN and an antigen (pg. 21, para. 0139); and that the invention contemplates that a subject can be prepared for a future encounter with an unknown antigen by administering to the subject a composition of an ORN of the invention (pg. 21, para. 0140). Thus, the invention of Forsbach encompasses use of the ORN in compositions as prophylactic to a viral infection, or as a vaccine, and thus anticipates instant claim 15.
Regarding claim 17-18; Forsbach teaches treating a subject having an immune system deficiency, such as suppressed CD4+ T-cell population; and thus anticipates instant claim 17. Forsbach teaches the method also contemplates the administration of one or more booster doses of the composition following an initial administration (pg. 21, para. 0139). Thus, Forsbach anticipates instant claim 18.
Conclusion
No claims are allowed. Claims 1-7, 9-11, 13, 15, 17-19, 21-22 and 26-27 are rejected; claim 25 is objected to as depending from a rejected claim.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642