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 .
DETAILED ACTION
Claims 1-19 are currently pending and under prosecution.
Claim Objections
Claim 9 is objected to because of the following informalities: claim 9 recites two commas after lipid particle. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-19 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. This is a WRITTEN DESCRIPTION rejection.
Claims 1-8 and 19 are drawn to a composition comprising an immunomodulating agent and a product comprising an mRNA construct encoding a therapeutic agent, wherein the mRNA construct is optionally encapsulated in a lipid nanoparticle. Claims 9-18 are drawn to a method of comprising administering to a subject a product comprising an mRNA construct encoding a therapeutic agent, wherein the mRNA construct is optionally encapsulated in a lipid nanoparticle, and administering to the subject an immunomodulating agent. Thus, the claims are drawn to a broad genus of (1) immunomodulating agents and (2) an mRNA construct encoding a therapeutic agent. The claims attempt to encompass every immunomodulating agent and every mRNA construct that encodes a therapeutic agent. No structure of the immunomodulating agent or mRNA construct that encodes a therapeutic agent is recited.
Dependent claims 2-4 and 10-12 recite the function of the immunomodulating agent reduced neutrophil expansion, lymphocyte trafficking, and monocyte trafficking. The claims recite the function of the immunomodulating agent only. No structure is recited.
Dependent claims 5 and 13 recites the immunomodulating agent blocks the function of interleukin-6 function and/or reduces the expression interulekin-6 in a cell. No structure of the immunomodulating agent that blocks interleukin-6 function is recited, nor any structure of any agent that reduced expression of IL-6 in a cell. The claims attempt to recite every agent that alters the function of IL-6, directly and indirectly.
Dependent claims 6 and 14 recites that the therapeutic agent is an antibody. The claims are drawn to the broad genus of “antibody”, no target or structure of the antibody is recited in the claims.
Thus, the written description is directed towards the following:
The broad genus of “immunomodulating agents”
The broad genus of “mRNA constructs that encode at therapeutic agent”
The broad genus of an immunomodulating agent that blocks the function of IL-6, and/or reduces the expression of IL-6 in a cell; and
The broad genus of an “antibody”
The instant specification discloses the following:
Immunomodulating agents: The instant specification discloses that the “immunomodulating agent” refers to a substance that stimulates or suppresses the immune system of a subject. Specific immunomodulating agents, such as monoclonal antibodies, cytokines, and vaccines, affect specific parts of the immune system. Nonspecific immunomodulating agents, such as BCG, affect the immune system in a general way. Some examples of immunomodulating agents include immunosuppressants, which are used to suppress the immune response in conditions such as autoimmunity and transplant rejection, and immunostimulants, which are used to enhance immune function in conditions such as cancer and chronic infections. Some exemplary immunomodulating agents are cytokines, interferons, interleukins, and BCG.” [¶ 0047]
IL-6: The instant specification discloses that an example of an immunomodulating agent is an agent that blocks the function of IL-6 in a cell and/or reduces the expression IL-6 in a cell. [¶ 0054] The instant specification discloses that the agent may be: (1) an IL-6 inhibitor, such as an IL-6 receptor monoclonal antibody or an anti-IL6 monoclonal antibody [0055], or (2) interferes with IL-6 gene transcription or translation, such as an RNAi or an siRNA. [¶ 0056]
mRNA: The instant specification discloses that the mRNA recited in the present disclose may encode any protein of interest. [¶ 0076-0080] ¶0079 discloses that the mRNA discloses a protein or a peptide which each of the nucleic acid sequences encodes a different peptide or protein. ¶ 0087 recites the structure of the mRNA which comprises a 5’UTR and 3’UTR, polyA sequence at 3’end and/or 5’ end. The UTR refers to the region flanking the protein coding sequence on either side of the 3’ side or the 5’ side of the RNA.
Therapeutic agent: The instant specification discloses that the therapeutic agent is an antibody, in which “an antibody unit typically consists of four polypeptide chains: two identical heavy chains and two identical light chains connected by disulfide bonds. Light chains consist of one variable domain VL and one constant domain CL, while heavy chains contain one variable domain VH and three to four constant domains, e.g., CH1, CH2, CH3. Immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG, and IgM, depending on the heavy chain constant domain amino acid sequence”. [¶ 0057] No specific antibodies or structures is disclosed.
State of the Art
With regards to mRNA constructs encoding therapeutic agents, Leong et al. (Revolutionizing immunization: a comprehensive review of mRNA vaccine technology and applications. Virol J. 2025 Mar 12;22(1):71) discloses the structure of the mRNA that encodes proteins: single-stranded molecule featuring a 5’ cap, a 3’ poly(A) tail, and open reading frame (ORF) flanked by untranslated regions (5’ and 3’ UTR). [pg 2, 2nd column, “mRNA vaccines”, Figure 1 below]
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Leong et al teaches that the open reading frame (ORF) is a critical determinant of the immunogenicity and translational efficiency. [pg 4, 1st and 2nd column – open reading frame] Leong teaches that the coding sequence for the target antigen is optimized to facilitate optimum protein folding and translation efficiency regulation. Furthermore, Klotchenko et al (mRNA-Encoded Antibodies: An Emerging Paradigm in Antiviral Protection. Biomolecules. 2026 Feb 13;16(2):297) teaches that exogenous mRNA sequences are obtained by intro transcription and that the typical structure includes a protein-coding sequenced flanked by 5’ and 3’ UTRs. [pg 10, section 4] Klotchenko teaches various approaches of mRNA design to ensure efficient expression of antibodies, such as dual HC/LC mRNA system, which enables co-expression of mRNA’s encoding both the heavy chain and the light chain of an immunoglobulin and single-chain mRNA. Klotchenko teaches different design strategies for antibody-encoding mRNA constructs, noting the sequences needed to encode antibody chains. [pg 13; Figure 2] Thus, the prior art demonstrates that each mRNA construct that encodes a specific target have unique sequence(s) and structure. With regards to “an antibody” as the therapeutic agent, the genus of antibodies is broad. By the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156 page 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3. Thus, it is not possible to predict the amino acid sequence of any antibody, which includes the sequences that translate into the antibody that is encoded by the mRNA construct.
With regards to immunomodulating agents, an immunomodulating agent is an agent that alters the body’s immune system to achieve a desired function. The class of immunomodulating agents is vast. Examples of these agents include but not limited to biologics, such as monoclonal antibodies, immunosuppressants, small drug inhibitors, and vaccines. The prior art teaches that immunomodulation as a whole is a challenging branch and there are limitations of the agents that fall under this mechanism, including chemical formulation. (See Strzelec et al (Immunomodulation-a general review of the current state-of-the-art and new therapeutic strategies for targeting the immune system. Front Immunol. 2023 Mar 9;14:1127704). The claims nor the specification do not provide any examples that attempt to claim all of the possible immunomodulating agents. With regards to targeting the function of IL-6, McElvaney et al (Lancet Respir Med 2021; 9: 643–54) teaches the known agents that block IL-6 or IL-6 receptor as shown in the Table on page 646. This table lists antibodies and small molecule inhibitors. Thus, the class of IL-6 inhibitors or blockers are known in the art. However, agents that reduce the expression of IL-6 in a cell, such as use of siRNA’s are not known. With regards to agents that reduce gene expressions, such as use of siRNA’s, Jia et al (Constructing the boundary between potent and ineffective siRNAs by MG-algorithm with C-features. BMC Bioinformatics. 2022 Aug 13;23(1):337) teaches that gene silencing effectiveness of RNAi relied on the siRNA efficacy in targeting a specific gene, so the efficacy prediction method constituted a huge challenge in selecting the potent siRNAs. Jia further teaches that there are no directly experimental evidences of utilizing learning algorithms to design potent siRNAS and that the reliability needs to be validated when they were used to define the similarity of siRNAS. [pg 1-2; Background]
To provide adequate written description and evidence of possession of the claimed composition comprising an immunomodulating agent and a product comprising an mRNA construct encoding a therapeutic agent, the instant specification can structurally describe representative agents, that function as claimed, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to screen for agents that function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future immunomodulating agent or mRNA construct yet to be discovered that may function as claimed.
Given the lack of representative examples to support the full scope of the claimed composition, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
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.
Claim 9 is 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 9 is indefinite in the use of the expression in parenthesis and quotations “(mRNA product)” in that it is not clear whether this recitation is intended to be part of the claim or not.
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.
Claim(s) 1, 5, 6, 8, 9, 13, 14 and 16 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Boeglin et al (WO2022155404 A1; Published: 1/21/2022).
Boeglin teaches a composition comprising an immunomodulating agent and a product comprising an mRNA construct encoding a therapeutic agent, wherein the mRNA construct is encapsulated in a lipid nanoparticle.
Of note, the instant specification defines an “immunomodulating agent” refers to a substance that stimulates or suppresses the immune system of a subject. [¶ 0047] Boeglin teaches composition of one or more mRNA’s that encode a heavy chain and a light chain of an antibody that bind to a protein target selected from IL-4, IL-5, IL-6, IL-9, IL-13, IL-25 or IL-33. [see at least claims 31-32, Abstract, 0093] The mRNA’s that encode a heavy chain and a light chain of an antibody, such as the IL-6 antibody, as taught by Boeglin stimulate or suppresses the immune system of a subject and falls under the scope of an “immunomodulating agent”
Regarding claims 5 and 13, Boeglin teaches that the immunomodulating agent blocks the function of interleukin-6 (IL-6). Boeglin teaches that least one of the mRNA’s blocks IL-6 or IL-6 receptor. [see at least 0090-0096] Regarding claims 6 and 14, Boeglin teaches the therapeutic agent is an antibody. Regarding claims 8-9 and 16, Boeglin teaches a method of administering the composition. Specifically, Boeglin teaches methods for administering one or more mRNAs, which falls within the scope of “simultaneously”. [claims 1-3, 0004, 0090, ] Regarding claims 7 and 15, Boeglin teaches the antibody is engineered to improve the half-life of the antibody. [0084]
Claim Rejections - 35 USC § 103
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.
Claim(s) 1-6, 8-14, 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Boeglin et al (WO2022155404 A1; Published: 1/21/2022), in view of Jarlborg (Systemic effects of IL-6 blockade in rheumatoid arthritis beyond the joints. Cytokine. 2022 Jan;149:155742).
The teachings of Boeglin are recited above in the 102 rejection. However, Boeglin does not specifically teach: (1) that the immunomodulating agent reduces neutrophil expansion, lymphocyte trafficking, or monocyte trafficking as recited in claims 2, 3, and 4, respectively, as well as, claims 10, 11, and 12, respectively; (2) measuring blood cell count and neutrophil count (as noted in claims 17 and 18), and (3) a kit comprising an immunomodulating agent and the mRNA construct as noted in claim 19.
Jarlborg et al teaches the systemic effects of IL-6 blockade, specifically effects regarding monocytes, neutrophils and lymphocytes. Jarlborg teaches that classic signaling involves binding to membrane-bound IL-6 receptor, and that the receptor is present on neutrophils, monocytes, and some lymphocytes. [pg 1, 1st column, 1st paragraph] Jarlborg also teaches that the trans-signaling pathway of IL-6 is also involved in endothelial activation and production monocyte chemoattract protein (MCP)-1, which favors transition from neutrophil to monocyte recruitment. Jarlborg also teaches that IL-6 trans-signaling promotes secondary accumulation of monocytes to the site of inflammation. [pg 1, 2nd column, 2nd paragraph] Jarlborg also teaches that trans-signaling pathway of IL-6 has a pivotal role on lymphocytes and adaptive immunity, and IL-6 is involved in CD4+ differentiation and induces rapid activation of effector functions in CD8+ T cells. [pg 2, 2nd column, 3rd paragraph] Jarlborg also teaches that neutrophils are closely involved in IL-6 biology and IL-6 blockade reduces neutrophil. [pg 3, 2nd column, 4th paragraph] Jarlborg also teaches measuring blood cell count and neutrophil counts when administering an IL-6 inhibitor, and teaches the levels needed to interrupt treatment or discontinue treatment. [Table 1]
It is noted that claims 2, 3, 4, and 10, 11, 12, require that the immunomodulating agent reduces neutrophil expansion, lymphocyte trafficking, or monocyte trafficking, respectively. This limitation would have been obvious to those of ordinary skill in the art because: (1) Boeglin teaches a composition comprising an immunomodulating agent, an mRNA product that encodes an IL-6 inhibitor, and second product comprising an mRNA construct encoding a therapeutic agent, (2) Jarlborg teaches that IL-6 has direct effects of neutrophils, monocytes and some lymphocytes as the IL-6 receptor is present on these cells, (3) Jarlborg teaches that IL-6 promotes monocytes and involved in CD4+ differentiation and CD8+ expansion, and (4) Jalborg also teaches that IL-6 blockade reduces neutrophil counts. Thus, given the known role of IL-6 on monocytes, neutrophils and lymphocytes, one of skilled in the art could have expected that blocking IL-6 will lead to the opposite effect of IL-6 which is reduced neutrophil expansion and lymphocyte and monocyte trafficking.
It is noted that claims 17 and 18 require measuring blood cell counts and neutrophil counts before and after administration of the immunomodulating agent. This limitation would have been obvious to those of ordinary skill in the art because: (1) Boeglin teaches administering a composition comprising an immunomodulating agent, an mRNA product that encodes an IL-6 inhibitor, and second product comprising an mRNA construct encoding a therapeutic agent, (2) Jarlborg also teaches that neutrophils are closely involved in IL-6 biology and IL-6 blockade reduces neutrophil, and (3) Jarlborg also teaches measuring blood cell count and neutrophil counts when administering an IL-6 inhibitor, and teaches the levels needed to interrupt treatment or discontinue treatment. Thus, given the known methods of administering the claimed composition, given the known effects of an immunomodulating agent, such as an IL-6 inhibitor, on blood cell count, and given the known methods of measuring before and after for dose adjustments or treatment discontinuation as taught by Jarlborg, one of skilled in the art could have pursued measuring blood cell counts and neutrophil counts, with a reasonable expectation of success.
Jarlborg et al teaches the systemic effects of IL-6 blockade, specifically effects regarding monocytes, neutrophils and lymphocytes. Jarlborg teaches that classic signaling involves binding to membrane-bound IL-6 receptor, and that the receptor is present on neutrophils, monocytes, and some lymphocytes. [pg 1, 1st column, 1st paragraph] Jarlborg also teaches that the trans-signaling pathway of IL-6 is also involved in endothelial activation and production monocyte chemoattract protein (MCP)-1, which favors transition from neutrophil to monocyte recruitment. Jarlborg also teaches that IL-6 trans-signaling promotes secondary accumulation of monocytes to the site of inflammation. [pg 1, 2nd column, 2nd paragraph] Jarlborg also teaches that trans-signaling pathway of IL-6 has a pivotal role on lymphocytes and adaptive immunity, and IL-6 is involved in CD4+ differentiation and induces rapid activation of effector functions in CD8+ T cells. [pg 2, 2nd column, 3rd paragraph] Jarlborg also teaches that neutrophils are closely involved in IL-6 biology and IL-6 blockade reduces neutrophil. [pg 3, 2nd column, 4th paragraph] Jarlborg also teaches measuring blood cell count and neutrophil counts when administering an IL-6 inhibitor, and teaches the levels needed to interrupt treatment or discontinue treatment. [Table 1]
It is noted that claim 19 requires the use of a kit comprising an immunomodulating agent and an mRNA construct encoding a therapeutic agent. This limitation would have been obvious to those of ordinary skill in the art because Boeglin teaches a composition comprising an immunomodulating agent and a product comprising an mRNA construct encoding a therapeutic agent, wherein the mRNA construct is encapsulated in a lipid nanoparticle. Thus, given the known use of kits and given the known composition comprising an mRNA construct encoding a therapeutic agent and an immunomodulating agent, one of skill in the art could have put together a kit with the claimed composition, with a reasonable expectation of success.
Claim(s) 1, 5-9, and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Boeglin et al (WO2022155404 A1; Published: 1/21/2022), in view of Vincent et al (Current strategies in antibody engineering: Fc engineering and pH-dependent antigen binding, bispecific antibodies and antibody drug conjugates, Biotechnol. J. 2012, 7, 1444–1450).
The teachings of Boeglin are recited above in the 102 rejection. However, Boeglin does not specifically teach the limitations of claims 7 and 15: the constant region of the antibody is engineered to improve the half-life.
Vincent teaches known methods of antibody engineering to improve the functionality of monoclonal antibodies and improve the clinical effectiveness. Vincent teaches strategies of antibody life-life extension, including modifying the Fc region of the antibody. [Abstract, pg 1445, 2nd column, 2nd paragraph]
It is noted that claims 7 and 15 require that antibody comprises a constant region which is engineered to improve the half-life of the antibody. This limitation would have been obvious to those of ordinary skill in the art because: (1) Boeglin teaches the antibody is engineered to improve the half-life of the antibody, and (2) Vincent teaches known methods of increasing half life of antibodies, which includes engineering a constant region of the antibody. Given the known need to increase half-life of antibodies to improve the effect of the antibody, and given known methods of engineering Fc regions of antibodies to extent the half-life, one of skilled in the art could have pursued engineering the constant region of the claimed therapeutic antibody, with a reasonable expectation of success.
Conclusion
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/SARAH A ALSOMAIRY/ Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600
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