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 .
Drawings
The drawings are objected to for the following reasons:
37 C.F.R. 1.84 states “Character of lines, numbers, and letters. All drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.”
In the current case, the drawings filed on 2/15/24 are not fully legible.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 10 and 39 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.
Claim 10 is directed to the compound or pharmaceutically acceptable salt thereof of claim 1, wherein the poly-dA nucleic acid sequence and/or poly-dT nucleic acid sequence comprises a mixture of dA and dT nucleic acid residues, wherein the poly-dA nucleic acid sequence comprises between 100% and 51% dA nucleic acid residues and between 0% and 49% dT nucleic acid residues or wherein the poly-dT nucleic acid sequence comprises between 100% and 51% dT nucleic acid residues and between 0% and 49% dA nucleic acid residues.
The metes and bounds of the claim cannot be clearly ascertained because the claim requires for the poly-dA and/or poly-dT sequence to comprise a mixture of dA and dT residues. However, the poly-dA would not be considered poly-dA if it comprises poly-dT residues and vise versa. Additionally, the claim allows 100% of poly dA residues, which would not allow any poly dT residues and therefore conflicts with the previous requirement in the claim for the mixture. The same applies for allowing 100% of poly dT residues and therefore no poly dA residues. The claim is therefore not definite. The same is true for claim 39 regarding poly dC and poly dG residues.
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.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], 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.
Claims 10 and 39 are 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.
Claim 10 is not considered to further limit the base claim and reads upon poly dA nucleic acids (100% poly dA residues) and poly dT nucleic acids (100% poly dT residues); and claim 39 is not considered to further limit the base claim and reads upon poly dC nucleic acids (100% poly dC residues) and poly dG nucleic acids (100% poly dGT residues).
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.
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1, 3-5, 10, 13, 15, 17, 23, 30, 32-34, 39, 42, 44, 50, 57, 71, and 75 are 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.
The claims are directed to poly-dA, poly-dT, ds poly-dA/poly-dT, poly-dC, poly-dG, or ds poly-dC/dG nucleic acid sequences of any length. The specification does not adequately describe the genus of sequences that have the structure to function as required. Each of the sequences can be of any length, i.e. 5 nt, which would not likely have the required function.
Claim 17 is directed to a compound comprising an “interferon stimulatory DNA (ISD) sequence” or an “immunostimulatory herpes simplex virus (HSV) sequence”.
Although the specification discloses specific species of ISDs as recited in claims 1 and 30, the specification does not adequately describe the structure required for the function and the species disclosed are not representative of the entire claimed genus.
Without further description of the specific structural requirements required for the function, one would not be able to readily envision which sequences are necessarily included or excluded from the recited genus of ISDs.
Additionally, with further description of the structure required for the function, one would not be able to readily envision with HSV sequences would necessarily have the function of being immunostimulatory.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
To achieve the desired function, Barbuto et al. teach that conjugation of pdA:dT to an antigen and teach that it has been shown that at least 40 base pairs of dA:dT are necessary for immune activation, with the degree of activation steadily increasing as a function of DNA length beyond that threshold (page 3) (instant claims 5, 27, and 34). The instant claims encompass sequences of any length. Although claims 5, 27, and 34 recite length limitations, the limitations are recited in the alternative and are not required for each strand of the ds compounds.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for nucleic acid sequences within the instant enormous genus that have the required function; or sequences that are ISDs or immunostimulatory HSV sequences. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Claim 57 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of inducing an immune response with specific nucleic acid sequences, does not reasonably provide enablement for a method of inducing an immune response against any possible antigen via delivery of any of the instantly recited agents of any length. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The claims are directed to a method of inducing an immune response against any possible antigen in a subject comprising broad systemic delivery (i.e. oral) any poly-dA and poly-dT dsDNA sequence of any length, any poly-dA or poly-dT sequence of any length, any poly-dG and poly-dC dsDNA of any length, or any poly-dG or poly-dC sequence of any length.
The specification does not draw an adequate nexus between delivery of any of these possible agents of any length and sequence via any means and the predictable outcome of inducing an immune response against any possible antigen.
To achieve the desired function, Barbuto et al. teach that conjugation of pdA:dT to an antigen and teach that it has been shown that at least 40 base pairs of dA:dT are necessary for immune activation, with the degree of activation steadily increasing as a function of DNA length beyond that threshold (page 3) (instant claims 5, 27, and 34). The instant claims encompass sequences of any length.
Even with regards to the agents to the agents of the specification of specific lengths, the specification does not demonstrate that introduction of any of the agents alone via any mode of delivery predictably induce an immune response against any possible antigen. The agents are non-specific and the immune response to the antigen depends upon the properties of the specific antigen. The specification has not demonstrated that any of the recited agents predictably induce an immune response against any antigen, but rather induces an immune response separately.
Although specific sequences have been shown to boost immune responses to certain co-administered antigens, making it useful as an adjuvant in those specific situations, the specification is not commensurate in scope with the instant claims.
The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of inducing an immune response to any possible antigen via broad delivery of any of the recited agents of any length encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of any possible agent of the instantly recited genus in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful induction of an immune response against any possible antigen. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the molecule in vivo, delivery of the molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 57 and 71 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Lavelle et al. (US 2021/0187104 A1).
Lavelle et al. teach: The present application relates to an adjuvant which is suitable to be used in vaccines or other immunogenic compositions. Specifically, the adjuvant promotes the induction of interleukin-1 (IL-1), type 1 interferons (IFNs), such as IFNα, and IFNβ, type 2 interferons, such as IFNγ and/or tumour necrosis factor (TNF) response, such as TNFα, and elicits or enhances an immune response, preferably in neonatal, juvenile or pediatric animal and/or human populations (abstract).
Lavelle et al. teach: [0016] the invention provides a vaccine composition comprising an antigen and an adjuvant which promotes the induction of cytokines such as interleukin-1, type 1 interferons (IFNs), such as IFNα, and IFNβ, type-2 interferons such as IFNγ and/or TNF response, such as TNFα (instant claim 71).
Lavelle et al. teach: [0034] According to a still preferred embodiment, the adjuvant is [0036] dsDNA mimic poly(deoxyadenylic-thymidylic) acid (Poly(dA:dT)) (instant claim 71).
Lavelle et al. teach: [0072] It will be understood that the adjuvant must be packaged for delivery to the cytoplasm of the cell. Suitable examples of delivery systems include [0073] Nanoparticle encapsulation; [0074] Polymer based nucleic acid nanocarriers; [0075] Cationic liposomes and polymers; [0076] Rigidified liposomes; [0077] Cell-penetrating peptide (CPP) complexes; [0078] Receptor targeting methods; and [0079] Ultra high affinity dsRNA binding protein carriers.
Lavelle et al. recite: 20. A method of eliciting or enhancing an immune response, optionally a desired antigen-specific immune response, in a subject, the method comprising administering to a neonatal, juvenile or pediatric animal subject a composition that comprises an adjuvant which promotes the induction of interleukin-1, type 1 interferons (IFNs), such as IFNα, and IFNβ, type-2 interferons such as IFNγ, and/or TNF response, such as TNFα.
21. The method of claim 20 wherein the adjuvant is a cytosolic nucleic acid sensor agonist or synthetic analog or mimic thereof selected from: double stranded DNA (dsDNA); double stranded RNA (dsRNA); cyclic guanosine monophosphate-adenosine monophosphate (cGAMP); or a synthetic analog or mimic thereof.
22. The method of claim 21 wherein the adjuvant is a nucleic acid sensing receptor agonist selected from: dsRNA mimic polyinosinic-polycytidylic acid (Poly(I:C)); dsDNA mimic poly(deoxyadenylic-thymidylic) acid (Poly(dA:dT));
Therefore, the claims are anticipated by Lavelle et al.
Claim(s) 27, 57, and 71 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Barbuto et al. (Nat Chem Biol. 2013 April ; 9(4): 250–256).
Barbuto et al. teach: Successful vaccines that elicit protective T-cell immunity contain not only protective antigen (or antigens) but also an adjuvant component that triggers innate immune activation and is necessary for immunogenicity (page 7).
Barbuto et al. teach that conjugation of pdA:dT to an antigen and teach that it has been shown that at least 40 base pairs of dA:dT are necessary for immune activation, with the degree of activation steadily increasing as a function of DNA length beyond that threshold (page 3).
Barbuto et al. teach a method of inducing an immune response by delivery of poly dA:dT to dendritic cells (title) in mice (abstract) (instant claim 57).
Therefore, the claim is anticipated by Barbuto et al.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3-5, 10, 13, 15, 17, 23, 30, 32-34, 39, 42, 44, 50, and 75 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lavelle et al. (US 2021/0187104 A1), in view of Lee et al. (Biochemistry, 1984, 23, 3277-3281), Sleep (Expert Opin. Drug Deliv., 2014, 12, 5, 793-812), Barbuto et al. (Nat Chem Biol. 2013 April ; 9(4): 250–256), and Latimer et al. (Nucleic Acids Research, 17, 1989, 1549-1561).
Lavelle et al. teach: The present application relates to an adjuvant which is suitable to be used in vaccines or other immunogenic compositions. Specifically, the adjuvant promotes the induction of interleukin-1 (IL-1), type 1 interferons (IFNs), such as IFNα, and IFNβ, type 2 interferons, such as IFNγ and/or tumor necrosis factor (TNF) response, such as TNFα, and elicits or enhances an immune response, preferably in neonatal, juvenile or pediatric animal and/or human populations (abstract).
Lavelle et al. teach: [0016] embodiment of the invention provides a vaccine composition comprising an antigen and an adjuvant which promotes the induction of cytokines such as interleukin-1, type 1 interferons (IFNs), such as IFNα, and IFNβ, type-2 interferons such as IFNγ and/or TNF response, such as TNFα (instant claim 71).
Lavelle et al. teach: [0034] According to a still preferred embodiment, the adjuvant is [0036] dsDNA mimic poly(deoxyadenylic-thymidylic) acid (Poly(dA:dT)) (instant claim 71).
Lavelle et al. teach: [0055] We have identified that activation of intracellular cytoplasmic PRRs with nucleic acid formulations, such as [0056] Poly(I:C) (double stranded RNA); [0057] Poly(dA:dT) (double stranded DNA); or [0058] direct STING ligand cGAMP elicits a robust innate immune response in neonatal and/or pediatric blood that is not only equal to that observed in adult blood but is in fact enhanced when compared to that of the adult.
The Poly(dA:dT) (double stranded DNA) comprises a strand that is 100% poly-dA an a strand that is 100% poly-dT (instant claim 10).
Lavelle et al. teach: [0059] Based on our findings, we propose that activating a family of intracellular cytosolic nucleic acid sensors belonging to the innate immune system in a format that would allow the nucleic acid to gain access to the intracellular cytoplasmic PRRs during the formulation of vaccines, or other immunogenic compositions, will allow for effective vaccination in a neonatal and/or pediatric population, due to the ability of the neonatal and infant immune system to respond to such stimuli.
Lavelle et al. teach: [0068] Advantageously, the use of these adjuvants in a format that will activate the intracellular cytosolic nucleic acid sensors in vaccine or other immunogenic formulations will provide age-appropriate “adjuvants” for vaccine-preventable diseases potentially eliminating the need for booster injections and preventing life-threatening invasive infection in early life. In this manner, the adjuvants of the invention are formulated to enter the cytosol so they can activate the intracellular cytosolic nucleic acid (CNA) sensor target of interest. For example, the adjuvant, such as Poly(I:C) or Poly(dA:dT), may be packaged in a delivery system, preferably a nanoparticle, cationic or polymeric delivery system, for delivery into cytoplasm of a cell. This is discussed below.
Lavelle et al. teach: [0071] Nucleic acids are not very efficient when administered alone, which means that the use of appropriate methods for in-vivo transfection of these molecules into targeted cells is fundamental. Examples of these techniques are the use of viral and non-viral vectors to transfer the nucleic acid to the cell’s nucleus. While viral vectors have demonstrated superior effectiveness for nucleic acid transfer, viral vectors have many drawbacks. Non-viral carrier (synthetic vector) delivery systems offer several advantages that have significantly advanced their development. These include improved biosafety and flexibility. They are also simpler to manufacture and modify compared to viral vectors.
Lavelle et al. teach: [0072] It will be understood that the adjuvant must be packaged for delivery to the cytoplasm of the cell. Suitable examples of delivery systems include [0073] Nanoparticle encapsulation; [0074] Polymer based nucleic acid nanocarriers; [0075] Cationic liposomes and polymers; [0076] Rigidified liposomes; [0077] Cell-penetrating peptide (CPP) complexes; [0078] Receptor targeting methods; and [0079] Ultra high affinity dsRNA binding protein carriers.
Lavelle et al. teach: [0080] Preferably, the adjuvant may be packaged in a nanoparticle, cationic or polymeric delivery system to facilitate delivery into cytoplasm of a cell.
Lavelle et al. teach: [0081] Cationic lipids and cationic polymers have been widely studied in the context of non-viral gene delivery systems. The discovery of lipofection has prompted the use of cationic lipids for nucleic acid delivery in-vitro and in-vivo. Cationic lipids form cationic liposomes that electrostatically bind to anionic nucleic acids, forming complexes (lipoplexes) that are taken up into cells by endocytosis.
Lavelle et al. teach: [0082] According to a preferred embodiment, Poly(I:C) or Poly(dA:dT) is packaged in a polymeric system that efficiently delivers the nucleic acid into the cytoplasm.
Formulation into a kit is considered an obvious means of packaging as a matter of design choice. The kit is considered obvious over the composition. Claim 75 does not recite any additional structural limitation.
Lavelle et al. teach: [0112] We have discovered that adjuvants which promote the induction of type 1 interferons can overcome the deficiency in interferon gamma production by peripheral blood mononuclear cells from animals over the first few months of life, preferably from 0-10 months. Specifically, we found that transfection of the adjuvant Poly (deoxyadenylic-thymidylic) acid (Poly(dA:dT)) promotes type 1 interferon dependent enhancement of interferon gamma production in PBMCs. This strategy provides a valuable means to enhance Th1 immune responses in neonatal cattle and facilitate the generation of improved vaccines/immunogenic compositions for animals in general.
Lavelle et al. recite:
20. A method of eliciting or enhancing an immune response, optionally a desired antigen-specific immune response, in a subject, the method comprising administering to a neonatal, juvenile or pediatric animal subject a composition that comprises an adjuvant which promotes the induction of interleukin-1, type 1 interferons (IFNs), such as IFNα, and IFNβ, type-2 interferons such as IFNγ, and/or TNF response, such as TNFα.
21. The method of claim 20 wherein the adjuvant is a cytosolic nucleic acid sensor agonist or synthetic analog or mimic thereof selected from: double stranded DNA (dsDNA); double stranded RNA (dsRNA); cyclic guanosine monophosphate-adenosine monophosphate (cGAMP); or a synthetic analog or mimic thereof.
22. The method of claim 21 wherein the adjuvant is a nucleic acid sensing receptor agonist selected from: dsRNA mimic polyinosinic-polycytidylic acid (Poly(I:C)); dsDNA mimic poly(deoxyadenylic-thymidylic) acid (Poly(dA:dT));
It would have been obvious for the nucleic acid sequence to be poly(dC:dG) instead of poly(dA:dT) as a matter of design choice because Lee et al. teaches that
poly(dG)-poly(dC) is immunogenic and that although most duplex DNAs that are in the “B” conformation are not immunogenic, one important exception is poly(dG)-poly(dC), which produces a good immune response even though, by many criteria, it adopts a conventional right-handed helix (abstract) (instant claims 30, 32, and 33). One would have had a reasonable expectation that poly(dC:dG) would be immunogenic as taught by Lee et al. in the method of Lavelle et al.
The Poly(dC:dG) (double stranded DNA) comprises a strand that is 100% poly-dC an a strand that is 100% poly-dG (instant claim 39).
Lavelle et al. do not teach incorporation of an albumin-binding domain.
However, it would have been obvious to incorporate an albumin-binding domain because Sleep teaches the benefits of incorporation of albumin-based fusions and conjugates for oral and pulmonary-based vaccines and delivery.
Sleep teaches: Albumin’s inherent biochemical and biophysical properties make it an ideal drug delivery platform. Recent advances in our understanding of albumin physiology and the improvement in albumin-based therapies strongly suggest that albumin-based therapies have a significant advantage over alternative technologies in terms of half-life, stability, versatility, safety and ease of manufacture. Given the importance of the albumin:FcRn interaction, the interpretation of the pharmacokinetic and pharmacodynamic pro files of albumin-based therapeutics with disturbed albumin:FcRn interaction may have to be reassessed. The FcRn receptor has additional functionality, especially in relation to immunology, antigen presentation and delivery of proteins across mucosal membranes, consequently albumin-based fusions and conjugates may have a future role in oral and pulmonary-based vaccines and drug delivery (page 793).
Sleep teaches: Due to its abundance and inherent properties, albumin possesses an extraordinary ligand-binding capacity and makes albumin the most important carrier/transporter protein in the human body for both endogenous and exogenous ligands, enabling some drugs to be available in quantities beyond their natural plasma solubility, decreasing their toxicity, lowering clearance rates and increasing circulatory half-life (page 795).
Therefore, there would been a motivation to incorporate an albumin binding domain at either end with the expectation of the delivery benefits taught by Sleep (instant claims 1,15, 17, 44, and 50).
Sleep teaches that dependent upon the nature of therapeutic molecule, de novo chemical synthesis of the drug with linker and thiol-compatible conjugation chemistry (page 800). Therefore, it would have been obvious to attach the albumin-binding domain via a linker as a matter of design choice (instant claims 23 and 50).
Lavelle et al. do not teach the length of the nucleic acid sequence. However, Barbuto et al. teach that conjugation of pdA:dT to an antigen and teach that it has been shown that at least 40 base pairs of dA:dT are necessary for immune activation, with the degree of activation steadily increasing as a function of DNA length beyond that threshold (page 3) (instant claims 5, 27, and 34). Therefore, it would have been obvious for the sequence to be at least 40 base pairs in length with a reasonable expectation of the degree of activation steadily increasing as a function of DNA length beyond that threshold.
Barbuto et al. teach: Successful vaccines that elicit protective T-cell immunity contain not only protective antigen (or antigens) but also an adjuvant component that triggers innate immune activation and is necessary for immunogenicity (page 7).
Lavelle et al. do not teach incorporation of phosphorothioates (instant claims 13 and 42). It would have been obvious to incorporate phosphorothioate modifications because Latimer et al. teaches that phosphorothioates increase stability in poly(dG):(dC) and poly(dA):(dT) (pages 1553-1553) and have a lower Tm (abstract). Therefore, one would have been motivated to incorporate phosphorothioate modifications with the reasonable expectation of the benefits taught by Latimer et al.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
Prosecution Insights