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 .
Claims 126-145 are pending and under consideration.
Information Disclosure Statement
The IDS filed 11-17-2023 had some references which were not considered.
Barclay was not considered because the journal article was not cited.
The international search report for PCT/US2016/054598 was not considered as it could not be found in the application contents.
Taylor et al. was crossed out because it was not provided and was not listed separately.
Battacharya et al. was not considered as page 1 was blacked out.
Claim Objections
Claim 133 is objected to because of the following informalities: The claim lacks a period at the end. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 136 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. Claim 136 depends from claim 135 but does not further limit the subject matter of claim 135 because the decrease in immune system activity comprises the same sustained activation or inhibiting of immune signals. 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 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 143 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. In claim 143, it’s not clear if the lipid nanoparticles comprise all of the lipids or if each lipid can be an alternative. For example, it’s known in the art that LNPs are typically composed of an ionizable lipid, cholesterol, PEGylated lipid, and a helper lipid such as distearoylphosphatidylcholine. (Hassett et all, Molecular Therapy, Vol. 15, April 2019). Thus, this may also be an improper Markush claim. Clarification is requested.
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.
Claim(s) 126-130, 134-137, and 141 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bedi et al. (US 2020/0115455, April 16, 2020).
As to claims 126, and 135-137 Bedi et al. teach [0039] treating an autoimmune disease in a subject comprising administering a pharmaceutical composition comprising a first domain that comprises an extracellular domain of TNFR2 capable of binding an TNFR2 ligand and a second domain comprising a portion of TGF-beta that is capable of binding a TGF-beta receptor [0005, 0024, 0083,0137] and a linker linking the first and second domain and comprising a hinge-CH2-CH3 Fc domain [0185]. Regarding claim 135-136, the administration in vivo would inherently cause a decrease in immune system activity comprising sustained activation of an immune inhibitory signal and/or sustained inhibition of an immune activating signal. "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Regarding claim 137, Bedi et al. [0217] teach that fusion proteins of the invention can be synthesized using recombination DNA technology well known in the art where the coding sequences of various portions of the fusion proteins can be linked together at the nucleic acid level. Bedi et al. further teach [0163] that the compositions of the invention can include the targeting moieties as peptides or those molecules “encoding” the same which encompasses administering nucleic acids encoding the polypeptides.
As to claim 134, Bedi et al. teach that the chimeric protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:104. Bedi’s chimeric protein (Db) is SEQ ID NO:51. The boxed sequences comprise the Fc (IgG1 CH2 CH3) domain.
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As to claim 127, Bedi’s chimeric protein (SEQ ID NO:51) has an extracellular domain of TNFR2 that comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:102.
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As to claim 128, Bedi’s chimeric protein (SEQ ID NO:51) comprises a portion of TGF-beta that is at least 95% identical to SEQ ID NO:103.
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As to claims 129-130, Bedi et al. exemplify a hinge CH2 CH3 Fc domain derived from IgG1 (see paragraph 11 above, boxed sequences). However, Bedi et al. also teaches [0183] that the antibody classes can be interchanged such as using IgG4 and that they can be human.
As to claim 141, Bedi et al. further teach [0204] that suitable unit dosage forms, include, but are not limited to powders, tablets, pills, capsules, lozenges, suppositories, patches, nasal sprays, injectables, implantable sustained-release formulations, lipid complexes, etc. This would encompass a liposome or lipoplex.
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) 131-133 are further rejected under 35 U.S.C. 103 as being unpatentable over Bedi et al. (US 2020/0115455, April 16, 2020) in view of Schreiber et al. (US 2019/0169249, published June 6, 2019) and Xu et al, Mabs, Vol. 11 (7), July 2019.
As set forth above, Bedi et al. teach a chimeric protein (SEQ ID NO:51) that comprises the Fc (IgG1 CH2 CH3) domain linker. Bedi et al. further teach [0185] teach that an antigen-binding antibody fragment, including single-chain antibody, may include the variable region(s) alone or in combination with the entirety or a portion of the following: hinge region, CH1, CH2, and CH3 domains. Bedi et al. further teach [0183] that immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds an antigen wherein the immunoglobulin can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or subclass of immunoglobulin molecule. As to claim 132, Bedi et al., teach that the linker further comprises [0188] an amino acid linker such as (GGGGS)n (SEQ ID NO: 123) wherein n is 1, 2, 3, 4, 5, 6, 7, or 8. For example, GGGGSGGGGSGGGGS (SEQ ID NO: 104). The latter encompasses a joining linker having an amino acid independently selected from SEQ ID NO:11.
Bedi et al. does not specifically teach linkers that are at least 95% identical to SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3 (Claim 131) or that the linker comprises two or more joining linkers wherein one joining linker is N terminal to the hinge-CH2-CH3 Fc domain and another joining linker is C terminal to the hinge-CH2-CH3 Fc domain (Claim 133).
Schrieber et al. teach chimeric proteins that are used to treat cancers and inflammatory diseases. Similar to Bedi et al., these chimeric proteins are separated by FC domains [0008] and can be inclusive of IgG1, IgG2, IgG3 and IgG4 [0075]. Further, Schrieber et al. teach [0086] that the linker may function to improve the folding and/or stability, improve the expression, improve the pharmacokinetics, and/or improve the bioactivity of the chimeric protein. Schrieber et al. teach IgG4 Fc domain linkers [Table 1 and below] that comprise CH2 and CH2 domains. The three FC domain linkers have approximately 98% homology between the three sequences. Further, SEQ ID Nos: 25-27 (below) are 100% identical to the claimed SEQ ID NO:1-3.
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Schreiber further teach [0081] that one or more joining linkers may be employed to connect an Fc domain in a linker. For example, [0081, 0090], a chimeric protein can have the formula ECD 1-Joining Linker 1-Fc Domain-Joining Linker 2-ECD 2. This encompasses two or more joining linkers, “wherein one joining linker is N terminal to the hinge-CH2-CH3 Fc domain and another joining linker is C terminal to the hinge-CH2-CH3 Fc domain. Schreiber et al. further teach [0075] that the Fc domain exhibits increased affinity for and enhanced binding to the neonatal Fc receptor (FcRn) wherein it is believed that binding to FcRn increases the in vivo half-life.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to substitute the IgG1 CH2-CH3 Fc linker domain of Bedi et al. with at least the IgG4 CH2-CH3 linker domain of SEQ ID NO:25 (100% identical to the claimed SEQ ID NO:1) of Schreiber et al. because Bedi et al. taught that the immunoglobulin subclasses can be of any type such as IgG4. Further, one would have been motivated to do so because Schreiber et al. teaches that the linker may function to improve the folding and/or stability, improve the expression, improve the pharmacokinetics, and/or improve the bioactivity of the chimeric protein. Further, it would be obvious to incorporate two or more Fc joining linkers because Schreiber et al. teaches that increased affinity and binding to the neonatal Fc receptor increases the in-vivo half-life. Also, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that the simple substitution of one known element for another to obtain predictable results is obvious unless its application is beyond that person's skill. Further, it would have been obvious to include IgG4 CH2-CH3 linker domains with at least 95% identity to SEQ ID:1 because both IgG1 and IgG4 are composed of two identical heavy chains and light chains with similar overall structures and a high degree of sequence homology in both heavy chain and light chain constant regions. (see Xu et al, page 1289, 1st column). Xu et al. further teach (page 1290) that alignment of the constant regions of IgG1 and IgG4 shows (Figure 1) there are a total of 24 residue differences distributed throughout the CH1 (seven residues), hinge region (six residues), and the CH2 and CH3 domains (11 residues total). The impact of these Fc region residues on IgG4 stability has been studied extensively by point mutating the IgG4 residues to that of a corresponding residue in the IgG1 backbone. Hence, it would have been obvious to include variant IgG4 CH2-CH3 linker domains with at least 95% identity to SEQ ID NO:1 (or 2 or 3) because one would have a reasonable expectation of success that such linkers would function similarly as the wildtype IgG4 CH2-CH3. A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See MPEP 2144.09.
Claim(s) 145 is further rejected under 35 U.S.C. 103 as being unpatentable over Bedi et al. (US 2020/0115455, April 16, 2020).
Bedi et al. teaches [0039] as set forth above and further teaches methods of treating autoimmune and inflammatory disorders or preventing rejection of grafted cells or tissue.
Bedi et al. does not specifically include such autoimmune diseases as irritable bowel syndrome, inflammatory bowel disease, Crohn’s disease or ulcerative colitis (Claim 145).
However, Bedi et al. teach [0128-0129] that the aberrant activation of self-reactive T cells and/or breakdown of the mechanisms of immune tolerance promotes the development of autoimmunity that results in various diseases including type I diabetes mellitus, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and rheumatoid arthritis. The targeted immunosuppressive antibodies and/or fusion proteins of the invention are designed to suppress unwanted or excessive immune or inflammatory responses and restore or promote immune tolerance. Accordingly, the compositions and methods of the invention have broad clinical relevance for the treatment of diverse autoimmune or inflammatory diseases and preventing the rejection of a transplanted cell, tissue, or organ grafts.
Thus, one of ordinary skill in the art at the time of filing would consider it prima facie obvious for Bedi et al. to include specific autoimmune disorders such as inflammatory bowel disease because Bedi et al. provides a nexus between the targeted immunosuppressive fusion proteins and their clinical relevance to treating specific autoimmune disorders such as inflammatory bowel disease. Further one would have been motivated to include other well-known autoimmune disorders such as Crohn’s disease, irritable bowel syndrome, and ulcerative colitis because the nature of Bedi’s invention is tied to suppressing unwanted or excessive immune or inflammatory responses.
Claim(s) 137-140, 142-144 are further rejected under 35 U.S.C. 103 as being unpatentable over Bedi et al. (US 2020/0115455, April 16, 2020) in view of Stadler et al., (Nature Med., Vol. 23, 2017) and Hassett et al. (Molecular Therapy, Vol. 15, April 2019).
Bedi et al. teach as set forth above and further teach [0004, 0034] that the encoded fusion proteins can be used to treat cancer by reversing immune tolerance.
Bedi et al. does not teach the nucleic acid comprises an mRNA or a modified mRNA
(mmRNA), wherein the mmRNA comprises one or more nucleoside modifications such as those listed in Claim 139 or wherein the mmRNA further comprises a 5’-cap and or a poly A tail (Claims 137-140). Bedi et al. also does not teach formulating the pharmaceutical composition as a lipid nanoparticle (LNP) wherein the lipid nanoparticles comprise lipids selected from an ionizable lipid, a structural lipid, cholesterol, and a polyethyleneglycol (PEG)-lipid and wherein the lipid nanoparticles comprise (a) a cationic lipid comprising from 50 mol % to 85 mol % of the total lipid present in the particle; (b) a non-cationic lipid comprising from 13 mol % to 49.5 mol % of the total lipid present in the particle; and (c) a conjugated lipid that inhibits aggregation of particles comprising from 0.5 mol % to 2 mol % of the total lipid present in the particle (Claims 142-144).
Hassett et al. teach, as of April 2019, that there existed a variety of technologies for vaccine development, including live and attenuated viruses, recombinant proteins, synthetic peptides, glycoconjugates, and nucleic acids. Nucleic-acid (DNA and mRNA)-based vaccines offer several advantages over other technologies. They can be rapidly produced with reduced development time and costs by using a common manufacturing platform and purification methods regardless of the antigen (introduction). Further, regarding administering polypeptides (or antibodies), Stadler et al. teach (1st column, page 815) that there are limitations- including poor stability, low serum half-life, and a tendency to aggregate over time. To address these challenges, Stadler et al. successfully generated the polypeptides in vivo in the patient using engineered mRNA. To prevent immune activation, Stadler incorporated modified nucleosides into in vitro–transcribed (IVT) mRNA by generating 1-methylpseudouridine-containing mRNAs encoding His-tagged bispecific antibodies against CD3 and one of three tumor-associated antigens (TAAs): claudin 6 (CLDN6), claudin 18.2, and the epithelial cell adhesion molecule (EpCAM) (page 815). Efficient translation of the modified mRNA was ensured by removing double-stranded RNA. Moreover, the 5′ and 3′ UTRs and the poly(A) tail were optimized for improved intracellular stability and translational efficiency. Figure 2 demonstrates the sustained plasma level of functional bi-(scFv)2 protein and elimination of advanced xenograft tumors upon treatment of mice with picomolar amounts of the bispecific polypeptides-encoding in vitro–transcribed mRNA. While Stadler et al. (for in vivo administration) formulated their mRNA in a lipid/polymer complex (page 818-TransIt-mRNA Transfection kit), the option to formulate the mRNA in other lipid-like particles was widely available. For example, Hassett et al. taught (page 2, 1st column) that the most clinically advanced lipid nanoparticles (LNP) contained the ionizable lipid MC3 and has been shown to be safe in humans after intravenous (IV) administration of siRNA. Their own vaccine trials with MC3-based LNPs for influenza gave 100% seroconversion with a 100-μg dose of modified mRNA. However, consistent with other vaccines, they observed mild to moderate local and systemic adverse events. Thus, they screened 30 novel LNPs (page 2, 2nd column), each containing a different ionizable lipid in place of MC3. Each LNP formulation maintained the same lipid-nitrogen-to-phosphate ratio (N:P) and molar composition of lipid components (ionizable lipid, cholesterol, phospholipid, and polytheylene glycol [PEG] lipid). For example, LNP formulations were dissolved (page 8, 2nd column) in ethanol at molar ratios of 50:10:38.5:1.5 (ionizable lipid:DSPC:cholesterol:PEG lipid). The authors concluded that the lead ionizable lipids showed improved biodegradability while maintaining immune titers compared to MC3. Further, the tolerability data suggest that this increased biodegradability leads to a reduction in injection site inflammation.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to have modified the treatment of cancer using the bispecific polypeptides of Beti et al. by re-formulating them into a mRNA vaccine as taught by Stadler et al. One would have been motivated to do so because Stadler et al. taught that there are well-known limitations of administering bispecific polypeptides including poor stability, low serum half-life, and a tendency to aggregate over time. Further, Hassett et al. taught that nucleic-acid (DNA and mRNA)-based vaccines offer several advantages over other technologies. They can be rapidly produced with reduced development time and costs by using a common manufacturing platform and purification methods regardless of the antigen. Further, one of ordinary skill in the art would have been motivated to modify the mRNA (such as by generating1-methylpseudouridine-containing mRNAs) because Stadler taught they help to prevent immune activation. (Hassett et al. also used modified mRNA- see Materials & Methods). Also, there is a high degree of predictability of success in adapting the mRNA technology as Stadler et al. demonstrated sustained plasma levels of functional bi-(scFv)2 protein and the elimination of advanced xenograft tumors in mice with picomolar amounts of the bispecific polypeptides-encoding in vitro–transcribed mRNA. Further, one of ordinary skill in the art would have been motivated to choose a lipid nanoparticle (NPL) as an intracellular delivery agent as it was well-known at the time that ionizable lipids were the primary driver of potency and that the most clinically advanced LNPs contained the ionizable lipid MC3 which had already been shown to be safe in humans. Hassett et al. taught that LNPs are typically composed of an ionizable lipid, cholesterol, PEGylated lipid, and a helper lipid such as distearoylphosphatidylcholine. However, use of NPLs containing MC3 is not without side effects including mild to moderate local and systemic adverse events. Thus, Hassett et al. screened and identified 30 novel LNPs each with the same molar composition of lipid components at 50:10:38.5:1.5 (ionizable lipid:DSPC:cholesterol:PEG lipid). Some of these NPLs (such as Lipid H) revealed a lower magnitude of inflammation and severity when compared to MC3. Thus, one of ordinary skill in the art would have recognized the advantages of using NPLs with these molar ratio compositions. Further, the tolerability data suggest that this increased biodegradability leads to a reduction in injection site inflammation.
No claim is allowed.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643