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 .
Election/Restrictions
Applicant’s election of the species of an siRNA including a nucleotide sequence of SEQ ID NO: 1 which hybridizes to an oligonucleotide encoding MMP13 in the reply filed on 11/10/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-39 are under examination.
Priority
This application claims benefit of 63/484,459 filed 02/10/2023.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See page 48, paragraph 00155, reciting “http://”.
Claim Objections
Claims 21 and 23 are objected to because of the following informalities: claim 21 recites “p38/MAPK”, “TNF-alpha NF-kB” and “IL-1”, and claim 23 recites “MMP13”, “MMP1”, “SOX5”, “NGF” and ”MK2”. For clarity, the full name of the protein/gene should be written out. 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.
Written Description Rejection
Claims 1-39 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-4,11-20,25-39 encompass treating a genus of inflammatory diseases in any subject in need thereof, comprising administering to the subject by any route of administration an effective amount of a conjugate comprising a genus of siRNA’s capable of inhibiting expression of a genus of proteins associated with the inflammatory disease, a genus of lipophilic ligands capable of binding albumin, and a genus of linkers attaching the siRNA to the lipophilic ligand, the linker comprising any branching molecule attached to the siRNA and any hydrophilic spacer attaching the branching molecule to the lipophilic ligand. Claim 2 recites multiple species for the route of administration. Claims 5-10 further limit the inflammatory disease to arthritis or an inflammatory state associated with traumatic injury, and claim 6 recites species of arthritis (osteoarthritis, rheumatoid arthritis, inflammatory arthritis, multi-joint arthritis, gout and psoriatic arthritis), however still encompass any route of administration and administering a genus of siRNAs capable of inhibiting expression of a genus of proteins associated with the inflammatory disease. Claims 15-20,28-34 and 39 recite further details of the linker in the conjugate and the lipophilic ligand. Claims 21-23 recite species of oligonucleotides encoding various proteins associated with inflammatory diseases that the siRNA is capable of hybridizing to, and claim 24 recites species of siRNA sequences (SEQ ID NOs: 1,2,3,4 or a combination thereof).
Regarding the state of the art of diseases associated with inflammation, Chen et al. (Oncotarget 2018, Vol. 9, No. 6, pp. 7201-7218) teach inflammatory pathways impact the pathogenesis of a number of chronic diseases, and involve common inflammatory mediators and regulatory pathways. Inflammatory stimuli activate intracellular signaling pathways that then activate production of inflammatory mediators. Primary inflammatory stimuli, including microbial products and cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), mediate inflammation through interaction with the TLRs, IL-1 receptor (IL-1R), IL-6 receptor (IL-6R), and the TNF receptor (TNFR) [20]. Receptor activation triggers important intracellular signaling pathways, including the mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB), and Janus kinase (JAK)- signal transducer and activator of transcription (STAT) pathways (page 7205, “Activation of inflammatory Pathways”). Chen et al. teach chronic inflammation occurs when acute inflammatory mechanisms fail to eliminate tissue injury, and may lead to a host of diseases, such as cardiovascular diseases, atherosclerosis, type 2 diabetes, rheumatoid arthritis, and cancers, and acute and chronic inflammation mediated tissue injury is observed in many organ systems, including the heart, pancreas, liver, kidney, lung, brain, intestinal tract, and reproductive system (page 7209, right column).
Regarding the genus of siRNA sequences capable of inhibiting expression of a protein associated with an inflammatory disease, Lu et al. (Advances in Genetics, Vol. 54, 2005, “In Vivo Application of RNA Interference: From Functional Genomics to Therapeutics”, pages 117-142) teach adoption of siRNA for functional genomics looking for inhibition of genes that can generate therapeutic benefits reversing pathological effects, often caused by overexpression of those same genes. However, the approach clearly depends on the effectiveness of siRNA delivery to modulate, very selectively, the expression of specific genes and, as a result, to induce physiological or pharmacological effects. A key requirement is identification of an effective site in the target mRNA sequence for siRNA accessibility (page 122, top paragraph). Therefore, Lu et al. shows the importance and requirement of identifying an effective site in the target mRNA sequence for the siRNA.
McSwiggen et al. (US 20090099121, Published 16 April 2009), teach compounds, compositions, and methods for treatment of diseases and conditions that respond to modulation of matrix metalloproteinase 13 (MMP13) gene expression and/or activity, including short interfering nucleic acid (siNA) and short interfering RNA (siRNA) molecules capable of mediating RNA interference against MMP13 gene expression and are useful for treating diseases and conditions that respond to modulation of MMP13 gene expression in a subject such as inflammatory diseases, disorders or conditions, including rheumatoid arthritis and osteoarthritis (paragraph 0003,0135-0137).
The instant specification only discloses 4 sequences for the siRNA, SEQ ID NO: 1,2,3,4 or a combination thereof (paragraph 0062). Page 61 of the instant specification shows that SEQ ID NO: 1 is the antisense sequence and SEQ ID NO: 2 is the sense sequence for the siRNA targeting mouse MMP13, and SEQ ID NO: 3 is the antisense sequence and SEQ ID NO: 4 is the sense sequence for the siRNA targeting Guinea Pig MMP13 and shows the chemical modifications of these sequences:
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Example 9 discloses Mouse and Guinea Pig MMP13 siRNA sequence screening including screening seven candidate siRNA sequences targeting different sites of the murine MMP13 gene and 4 candidate siRNA sequences targeting different sites of the guinea pig MMP13 gene, and that lead sequences were made into a 19-mer and formulated with stabilization chemistry i.e., “zipper” (paragraph 00143). The specific sequences screened are not disclosed and this example does not disclose that the lead sequences are SEQ ID NOs: 1-4.
Example 9 discloses an in vivo therapeutic study of siMMP13<(EG18L)2 in a post-traumatic osteoarthritis (PTOA) mechanical loading mouse model (paragraph 00157), and in a Guinea pig anterior cruciate ligament model by intravenous administration (paragraph 00162). Results of the experiments are found on pages 56-57, and that the example conjugate, si<(EG18L)2 and the modified nucleotides aided properties of the siRNA including stability in synovial fluid and in-vitro carrier-mediated silencing (Fig. 1A,1B,1C,1D) and knockdown of murine MMP13 (Fig 1F) and binding to albumin in OA and RA human synovial fluid (Fig 1E) and that regular siRNA without lipophilic albumin-binding moieties did not have any appreciable MMP13 knockdown (Fig. 1F) or binding of albumin in human synovial fluid (Fig. 1E) (paragraph 00170).
The conjugate was assessed in vivo in different inflammatory disease models and demonstrated preferential accumulation, retention and silencing of a target gene in an injured joint model of PTOA as shown in Fig. 2A-2I, 3A-3G, 4A-4G and 5A-5H. The conjugate also accumulated and had activity in all joints in a mouse model of rheumatoid arthritis (Fig. 6A-6G, 7A-7D, 8A-8G, 9A-9E) and that in both models intravenous delivery of the siRNA conjugate yielded accumulation in the affected joint, and the conjugate showed effective silencing in a guinea pig anterior cruciate ligament transection model (Fig. 10A-10F) (paragraph 00171).
When designed against matrix metalloproteinase 13 (MMP13), the siRNA conjugate robustly silenced MMP13 expression in the joints. In both the PTOA and RA models, silencing of MMP 13 by systemic, intra-venous, treatment provided significant therapeutic benefits in terms of reducing joint inflammation, reducing cartilage loss, reducing synovial hyperplasia, maintaining bone homeostasis and reducing joint pressure sensitivity (pain). In-vivo subcutaneous studies (FIG. 11A - FIG. 11 C) show useful delivery and activity of siMMP13<(EG18L)2 at high doses and/or with the use of excipients. In-vivo local, intra-articular studies also show useful delivery, retention, and activity of siMMP 13<(EG18L)2 (FIG. 12A - FIG. 12F).
Therefore, the specification discloses methods of treating osteoarthritis, rheumatoid arthritis, post-traumatic osteoarthritis in a subject comprising administering by local, intra-articular, and intravenous administration, the conjugate of the siRNA of SEQ ID NOs: 1,2,3,4 (having the specific chemical modifications disclosed by these sequences described above) or combination thereof which targets mouse or guinea pig MMP13 conjugated to (EG18L)2 results in treatment of osteoarthritis, rheumatoid arthritis. However, as explained above, the instant claims directed to encompass treating any inflammatory disease (even inflammatory diseases that are not arthritis-related) with any siRNA sequence that is capable of inhibiting expression of any protein associated with any inflammatory disease which encompasses millions of possible sequences towards many target proteins, as well as encompassing many different structures of the lipophilic ligand, and linker of the conjugate, which only correspond in some undefined way to specifically instantly disclosed chemicals. The instant specification lacks chemical structural information for what they are and chemical structures are highly variant and encompass a myriad of possibilities. The specification provides insufficient written description to support the genus encompassed by the claim. Note: MPEP 2163.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, (Fed. Cir. 1991), makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Univ. of Rochester v. G.D. Searle, 69 USPQ2d 1886, 1892 (CAFC 2004), further supports this by stating that:
The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. A description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) described even in terms of its functioning of lessening inflammation of tissues fails to distinguish any steroid from others having the same activity or function. A description of what a material does, rather than of what it is, usually does not suffice…. The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described. (Emphasis added).
With the exception of the above treatment method using the specifically disclosed chemical structures, the skilled artisan cannot envision the detailed chemical structure of the encompassed siRNA sequences and structures of the conjugate regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird, 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. It is noted that only 4 siRNA sequences that target mouse or guinea pig MMP13, and none targeting human MMP13 or any other species have been provided. Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Furthermore, to the extent that a functional description can meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle, 68 USPQ2d 1424, 1432 (DC WNY 2003). Therefore, the specification does not show the required structure-function correlation for the recited genus of siRNA sequences capable of inhibiting the expression of a genus of proteins associated with a genus of inflammatory diseases, and that is conjugated to a genus of lipophilic ligands and linkers comprising a branching molecule attached to the siRNA and hydrophilic spacer attaching the branching molecule to the lipophilic ligand, and has the recited function of treating a genus of inflammatory diseases in a subject.
Therefore, only the above chemically structurally defined chemicals, but not the full breadth of the claim(s) meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC § 112 is severable from its enablement provision. (See page 1115.)
Claim Rejections-Scope of Enablement
Claims 1-39 are 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 treating osteoarthritis, rheumatoid arthritis or post-traumatic osteoarthritis in a subject in need thereof, comprising administering by local, intra-articular, and intravenous administration, the conjugate comprising the siRNA of instant SEQ ID NOs: 1,2,3 or 4 or a combination thereof (having the specific chemical modifications disclosed by these sequences described above) which targets mouse or guinea pig MMP13 conjugated to (EG18L)2 , does not reasonably provide enablement for a method of treating a genus of inflammatory diseases in a subject in need thereof, comprising administering by a genus of routes of administration, an effective amount of a conjugate comprising a genus of siRNA’s capable of inhibiting expression of a genus of proteins associated with the genus of inflammatory diseases; a lipophilic ligand capable of binding albumin; and a linker comprising a branching molecule attached to the siRNA and a hydrophilic spacer attaching the branching molecule to the lipophilic ligand. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessary needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
The Breadth of the Claims and The Nature of the Invention
Claims 1-4,11-20,25-39 encompass treating a genus of inflammatory diseases in any subject in need thereof, comprising administering to the subject by any route of administration an effective amount of a conjugate comprising a genus of siRNA’s capable of inhibiting expression of a genus of proteins associated with the inflammatory disease, a genus of lipophilic ligands capable of binding albumin, and genus of linkers attaching the siRNA to the lipophilic ligand, the linker comprising any branching molecule attached to the siRNA and any hydrophilic spacer attaching the branching molecule to the lipophilic ligand. Claim 2 recites multiple species for the route of administration. Claims 5-10 further limit the inflammatory disease to arthritis or an inflammatory state associated with traumatic injury, and claim 6 recites species of arthritis (osteoarthritis, rheumatoid arthritis, inflammatory arthritis, multi-joint arthritis, gout and psoriatic arthritis) however still encompass any route of administration and administering a genus of siRNAs capable of inhibiting expression of a genus of proteins associated with the inflammatory disease. Claims 15-20,28-34 and 39 recite further details of the linker in the conjugate and the lipophilic ligand. Claims 21-23 recite species of oligonucleotides encoding various proteins associated with inflammatory diseases that the siRNA is capable of hybridizing to, and claim 24 recites species of siRNA sequences (SEQ ID NOs: 1,2,3,4 or a combination thereof).
The State of the Prior Art
Regarding the state of the art of diseases associated with inflammation, Chen et al. (Oncotarget 2018, Vol. 9, No. 6, pp. 7201-7218) teach inflammatory pathways impact the pathogenesis of a number of chronic diseases, and involve common inflammatory mediators and regulatory pathways. Inflammatory stimuli activate intracellular signaling pathways that then activate production of inflammatory mediators. Primary inflammatory stimuli, including microbial products and cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), mediate inflammation through interaction with the TLRs, IL-1 receptor (IL-1R), IL-6 receptor (IL-6R), and the TNF receptor (TNFR) [20]. Receptor activation triggers important intracellular signaling pathways, including the mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB), and Janus kinase (JAK)- signal transducer and activator of transcription (STAT) pathways (page 7205, “Activation of inflammatory Pathways”). Chen et al. teach chronic inflammation occurs when acute inflammatory mechanisms fail to eliminate tissue injury, and may lead to a host of diseases, such as cardiovascular diseases, atherosclerosis, type 2 diabetes, rheumatoid arthritis, and cancers, and acute and chronic inflammation mediated tissue injury is observed in many organ systems, including the heart, pancreas, liver, kidney, lung, brain, intestinal tract, and reproductive system (page 7209, right column).
Regarding the genus of siRNA sequences capable of inhibiting expression of a protein associated with an inflammatory disease, Lu et al. (Advances in Genetics, Vol. 54, 2005, “In Vivo Application of RNA Interference: From Functional Genomics to Therapeutics”, pages 117-142) teach adoption of siRNA for functional genomics looking for inhibition of genes that can generate therapeutic benefits reversing pathological effects, often caused by overexpression of those same genes. However, the approach clearly depends on the effectiveness of siRNA delivery to modulate, very selectively, the expression of specific genes and, as a result, to induce physiological or pharmacological effects. A key requirement is identification of an effective site in the target mRNA sequence for siRNA accessibility (page 122, top paragraph). Therefore, Lu et al. shows the importance and requirement of identifying an effective site in the target mRNA sequence for the siRNA.
McSwiggen et al. (US 20090099121, Published 16 April 2009), teach compounds, compositions, and methods for treatment of diseases and conditions that respond to modulation of matrix metalloproteinase 13 (MMP13) gene expression and/or activity, including short interfering nucleic acid (siNA) and short interfering RNA (siRNA) molecules capable of mediating RNA interference against MMP13 gene expression and are useful for treating diseases and conditions that respond to modulation of MMP13 gene expression in a subject such as inflammatory diseases, disorders or conditions, including rheumatoid arthritis and osteoarthritis (paragraph 0003,0135-0137).
The Level of Predictability in the Art
The instant claimed invention is highly unpredictable due to the claims encompassing treating a large genus of inflammatory diseases in a subject by a genus of routes of administration and administering a conjugate comprising a genus of siRNAs capable of inhibiting expression of a large genus of proteins associated with the inflammatory disease. As shown above in the state of the art, as taught by Chen et al., chronic inflammation may lead to a host of diseases, such as cardiovascular diseases, atherosclerosis, type 2 diabetes, rheumatoid arthritis, and cancers, and acute and chronic inflammation mediated tissue injury is observed in many organ systems, including the heart, pancreas, liver, kidney, lung, brain, intestinal tract, and reproductive system. Depending on the type of inflammatory disease and the affected tissue or organ, the siRNA would need to be administered by a particular route of administration that would allow the siRNA to be delivered to the appropriate tissue or organ to achieve the desired result. It would also be unpredictable, given the millions of encompassed siRNA sequences capable of inhibiting expression of a protein associated with the inflammatory disease, that any siRNA sequence would be capable of inhibiting expression of the protein associated with the inflammatory disease and result in the therapeutic effect.
The Amount of Direction Provided by the Inventor and
The Presence or Absence of Working Examples
Regarding claims 1-39, the specification does not enable any person skilled in the art to which it pertains to make and/or use the invention commensurate in scope with the claims. The instant specification only discloses 4 sequences for the siRNA, SEQ ID NO: 1,2,3,4 or a combination thereof (paragraph 0062). Page 61 of the instant specification shows that SEQ ID NO: 1 is the antisense sequence and SEQ ID NO: 2 is the sense sequence for the siRNA targeting mouse MMP13, and SEQ ID NO: 3 is the antisense sequence and SEQ ID NO: 4 is the sense sequence for the siRNA targeting Guinea Pig MMP13 and shows the chemical modifications of these sequences:
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Example 9 discloses Mouse and Guinea Pig MMP13 siRNA sequence screening including screening seven candidate siRNA sequences targeting different sites of the murine MMP13 gene and 4 candidate siRNA sequences targeting different sites of the guinea pig MMP13 gene, and that lead sequences were made into a 19-mer and formulated with stabilization chemistry i.e., “zipper” (paragraph 00143). The specific sequences screened are not disclosed and this example does not disclose that the lead sequences are SEQ ID NOs: 1-4. Example 9 discloses an in vivo therapeutic study of siMMP13<(EG18L)2 in a post-traumatic osteoarthritis (PTOA) mechanical loading mouse model (paragraph 00157), and in a Guinea pig anterior cruciate ligament model by intravenous administration (paragraph 00162). Results of the experiments are found on pages 56-57, and that the example conjugate, si<(EG18L)2 and the modified nucleotides aided properties of the siRNA including stability in synovial fluid and in-vitro carrier-mediated silencing (Fig. 1A,1B,1C,1D) and knockdown of murine MMP13 (Fig 1F) and binding to albumin in OA and RA human synovial fluid (Fig 1E) and that regular siRNA without lipophilic albumin-binding moieties did not have any appreciable MMP13 knockdown (Fig. 1F) or binding of albumin in human synovial fluid (Fig. 1E) (paragraph 00170). The conjugate was assessed in vivo in different inflammatory disease models and demonstrated preferential accumulation, retention and silencing of a target gene in an injured joint model of PTOA as shown in Fig. 2A-2I, 3A-3G, 4A-4G and 5A-5H. The conjugate also accumulated and had activity in all joints in a mouse model of rheumatoid arthritis (Fig. 6A-6G, 7A-7D, 8A-8G, 9A-9E) and that in both models intravenous delivery of the siRNA conjugate yielded accumulation in the affected joint, and the conjugate showed effective silencing in a guinea pig anterior cruciate ligament transection model (Fig. 10A-10F) (paragraph 00171). When designed against matrix metalloproteinase 13 (MMP13), the siRNA conjugate robustly silenced MMP13 expression in the joints. In both the PTOA and RA models, silencing of MMP 13 by systemic, intra-venous, treatment provided significant therapeutic benefits in terms of reducing joint inflammation, reducing cartilage loss, reducing synovial hyperplasia, maintaining bone homeostasis and reducing joint pressure sensitivity (pain). In-vivo subcutaneous studies (FIG. 11A - FIG. 11 C) show useful delivery and activity of siMMP13<(EG18L)2 at high doses and/or with the use of excipients. In-vivo local, intra-articular studies also show useful delivery, retention, and activity of siMMP 13<(EG18L)2 (FIG. 12A - FIG. 12F).
Therefore, the specification discloses methods of treating osteoarthritis, rheumatoid arthritis, post-traumatic osteoarthritis in a subject comprising administering by local, intra-articular, and intravenous administration, the conjugate of the siRNA of SEQ ID NOs: 1,2,3,4 (having the specific chemical modifications disclosed by these sequences described above) or combination thereof which targets mouse or guinea pig MMP13 conjugated to (EG18L)2 results in treatment of osteoarthritis, rheumatoid arthritis.
The Quantity of Experimentation Necessary
Regarding claims 1-39, in light of the unpredictability surrounding the breadth of the claimed method, one wishing to practice the presently claimed invention would be unable to do so without engaging in undue experimentation. The encompassed treatment method would need to be tested in various cell, tissue or animal models that correspond to the inflammatory diseases encompassed by the instant claims, as well as millions of possible siRNA sequences that correspond to different target proteins associated with inflammatory diseases and attach these sequences to different lipophilic ligands and linkers comprising branching molecules and hydrophilic spacers to form a conjugate and determine if the recited method is capable of treating all of the encompassed inflammatory diseases. As stated above, the specification only shows 4 siRNA sequences targeting MMP13 in osteoarthritis, rheumatoid arthritis or post-traumatic osteoarthritis model and the therapeutic effect thereof, as well as the specific lipophilic ligand and linker being (EG18L)2. Therefore, given the lack of guidance present in the specification for the recited method of treating, further experimentation would be required and would be considered undue.
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
After applying the Wands factors and analysis to claims 1-39, in view of the applicant’s entire disclosure, it is concluded that the specification is not enabled for the full scope as discussed above. Therefore, claims 1-39 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to use the invention commensurate in scope with these claims.
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.
Claims 1-7,10,11,15-19,21-23,25-26,28-33,35-37 and 39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Colazo et al. (Albumin-hitchhiking MMP13 siRNA Conjugate (siMMP13< (EG18L)2) for the Treatment of Rheumatic Disease 37th Annual MD/PhD Conference July 8-10,2022), cited on an IDS dated 06/05/2023.
Claim Interpretation: the wherein clauses in claims 3,4,10 and 35-37 are not being treated as a limitation because the “wherein clauses” in a method claim are not given weight when it simply expresses the intended results of a process step positively recited. See MPEP 2111.04.
Regarding claims 1-7,10,15-19,21-23,28-33,35-37 and 39, Colazo et al. teach a chemically stabilized MMP13 siRNA conjugate, siMMP13<(EG18L)2 which spontaneously binds albumin ‘in situ’. Colazo et al. teach for albumin-binding abilities, a splitter phosphoramidite (< ) (to allow for diacyladdition i.e., 2 lipid tails) at the 5ʹ end of the sense strand was added followed by 3 repeats of a hexa-ethylene glycol (EG) phosphoramidite. Thus, 18 EGs were added prior to each eighteen-carbon (C18)acyl (2x, L2 nomenclature) (Methods). Therefore, the siRNA conjugate of Colazo meets the structural limitations of claims 1-7,10,15-19,21-23,28-33,35-37 and 39 regarding the lipophilic ligand, and the linker comprising a branching molecule (splitter phosphoramidite) and hydrophilic spacer regarding the repeats of hexa-ethylene glycol and 18 EGs added prior to each C18 acyl, and which comprises two independent lipids including a C18 hydrocarbon chain. Colazo et al. teach an overload-induced osteoarthritis mouse model and serum transfer arthritis mouse model was used for OA and RA studies (Methods) and shows joint delivery of siMMP13<(EG18L)2 , in a mechanical overload model of osteoarthritis (Fig. 1A). Results showed siMMP13< (EGL) showed preferential delivery to OA knees/K/BxN hindpaws over healthy knees/hindpaws, and in the K/BxN model, siMMP13< (EGL) reached/treated multiple joints including forepaws knees, and hindpaws (Figure 3). siMMP13< (EGL) treatment was safe, provided potent MMP13 mRNA/protein knockdown, provided joint pain benefits, reduced arthritis clinical score,reduced arthritis-related genes, provided joint protection, and performed better than or equal to gold standard clinical controls.
Regarding claim 11, Colazo et al. teach the dose of the siRNA therapeutic is 10 mg/kg (Fig. 3).
Regarding claims 25-26, Colazo et al. teach the siRNA has alternating 2’-OMe and 2’F ribosugar modifications to stabilize against endonucleases and phosphorothioate linkages on the backbone to block exonucleases (Methods).
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.
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.
Claims 1-8,10,11,13-19,21-23,25-30,32 and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over McSwiggen et al. (US 20090099121, Published 16 April 2009) in view of Sarett et al. (PNAS Published 24 July 2017, E6490-E6497), cited on an IDS dated 06/05/2023.
Claim Interpretation: the wherein clauses in claims 3,4,8 and 10 are not being treated as a limitation because the “wherein clauses” in a method claim is not given weight when it simply expresses the intended results of a process step positively recited. See MPEP 2111.04.
Regarding claims 1,5-7,21 and 23, McSwiggen et al. teach compounds, compositions, and methods for treatment of diseases and conditions that respond to modulation of matrix metalloproteinase 13 (MMP13) gene expression and/or activity, including short interfering nucleic acid (siNA) and short interfering RNA (siRNA) molecules capable of mediating RNA interference against MMP13 gene expression and are useful for treating diseases and conditions that respond to modulation of MMP13 gene expression in a subject such as inflammatory diseases, disorders or conditions, including rheumatoid arthritis and osteoarthritis (paragraph 0003,0135-0137). McSwiggen et al. teach a composition comprising an siRNA molecule of the invention in a pharmaceutically acceptable carrier or diluent, and a method of treating comprising administering to the subject a composition of the invention (paragraph 0150). Regarding the meaning of “siNA” used in McSwiggen et al., paragraph 0199 of McSwiggen et al. teach “As used herein, the term siNA is meant to be equivalent to other terms used to describe nucleic acid molecules that are capable of mediating sequence specific RNAi, for example short interfering RNA (siRNA)…” (paragraph 0199).
McSwiggen et al. teach the siNA capable of mediating RNAi against MMP13 can be chemically modified and include a conjugate which can be attached to the chemically modified siRNA molecule via a biodegradable linker.
Regarding the effective amount, the instant specification teaches a suitable dose will often be in the range of 0.01-1000 mg/kg, such as about 0.1 to about 100 mg/kg (paragraph 0091). McSwiggen et al. teach a pharmaceutically effective dose is that dose required to prevent, inhibit, the occurrence or treat of a disease state, and generally an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered (paragraph 0341).
McSwiggen et al. do not teach that the conjugate comprises a lipophilic ligand capable of binding albumin and a linker attaching the siRNA to the lipophilic ligand, the linker comprising a branching molecule attached to the siRNA and a hydrophilic spacer attaching the branching molecule to the lipophilic ligand.
Before the effective filing date, Sarett et al. taught that clinical translation of therapies based on small interfering RNA (siRNA) is hampered by siRNA’s comprehensively poor pharmacokinetic properties which necessitates molecule modifications and complex delivery strategies (Abstract). Sarett et al. taught an siRNA conjugated to a diacyl lipid moiety (siRNA-L2) which rapidly binds albumin in situ and in comparison to unmodified siRNA exhibited 5.7 fold increase in circulation half-life, 8.6 fold increase in bioavailability and reduced renal accumulation (Abstract). Sarett et al. taught that in situ targeting of albumin following delivery is a viable strategy because endogenous albumin is the most abundant serum protein, and has a circulation half-life of around 20 days, and is a natural carrier of and has high affinity for poorly soluble lipids (page E6491, left column). Sarett et al. taught the strategic choice of modification with an albumin-binding lipid has potential to confer additional advantages in siRNA stability and cell membrane interactions for uptake and endosomal escape in addition to circulation persistence, tissue penetration and bio-distribution (page E6491, left column). Sarett et al. taught to synthesize the siRNA conjugated to a diacyl lipid moiety, amine modified siRNA was reacted with an NHS ester/dibenzocylooctyne heterobifunctional cross-linker and conjugated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000] (DSPE-PEG2000-azide) to generate siRNA-L2 also shown in Fig 1A.
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The SI Appendix, Fig SIA of the full reaction is shown below:
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It is noted that the final structure of the conjugate shown in the SI Appendix, is almost identical to that shown in instant Fig. 1B shown below:
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Therefore, Sarett et al. taught a lipophilic ligand capable of binding albumin and a linker attaching the siRNA to the lipophilic ligand comprising a branching molecule attached to the siRNA and a hydrophilic spacer attaching the branching molecule to the lipophilic ligand.
Regarding claim 2, McSwiggen et al. teach the nucleic acid molecules of the invention are administered via direct injection to the affected site (e.g. affected joint or associated synovial fluid in cases of treating rheumatoid arthritis or osteoarthritis) (paragraph 0327).
Regarding claims 3,4,8 and 10, see the claim interpretation above regarding the wherein clauses not given weight when it simply expresses the intended results of a process step positively recited.
Regarding claim 11, McSwiggen et al. teach a pharmaceutically effective dose is that dose required to prevent, inhibit, the occurrence or treat of a disease state, and generally an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered (paragraph 0341).
Regarding claim 13, McSwiggen et al. teach delivery systems of the invention can contain excipients such as enhancers and other vehicles (e.g., polyethylene glycol) (paragraph 0331), and sucrose sweetening agents (paragraph 0345,0349).
Regarding claim 14, McSwiggen et al. teach the subject is human (paragraph 0227).
Regarding the limitations of the branching molecule and hydrophilic spacer in claims 15-19, these limitations have been discussed above in Sarett et al.
Regarding claim 22, McSwiggen et al. teach MMPs act as regulatory molecules, both by functioning in enzyme cascades and by processing matrix proteins to generate fragments with enhanced or reduced biological effects and as a family the MMPs are capable of breaking down numerous extracellular matrix components (paragraphs 0365 and 0367), and the MMP family includes MMP13 (paragraph 0366).
Regarding claims 25 and 26, McSwiggen et al. teach stabilizing chemical modifications including phosphorothioate internucleotide linkages, 2′-deoxyribonucleotides, 2′-O-methyl ribonucleotides, 2′-deoxy-2′-fluoro ribonucleotides, “universal base” nucleotides, “acyclic” nucleotides, 5-C-methyl nucleotides, and terminal glyceryl and/or inverted deoxy abasic residue incorporation and these chemical modifications, when used in various siNA constructs, (e.g., RNA based siNA constructs), are shown to preserve RNAi activity in cells while at the same time, dramatically increasing the serum stability of these compounds, and that multiple (greater than one) phosphorothioate substitutions are well-tolerated and confer substantial increases in serum stability for modified siNA constructs (paragraph 0034). Table IV on page 63 also shows stabilizing chemistries for chemically modified siRNA constructs.
Regarding claim 27, McSwiggen et al. teach the siNA molecule comprises an antisense strand having about 15 to about 30 nucleotides and a sense strand having about 15 to about 30 nucleotides (paragraph 0030).
Regarding the limitations of the lipophilic ligand in claims 28-30 and 32, these limitations have been discussed above in Sarett et al.
Regarding the limitations of claims 35-37, see the claim interpretation above regarding the wherein clauses not given weight when it simply expresses the intended results of a process step positively recited.
Therefore, it would have been obvious to one of ordinary skill in the art to have modified the MMP13 siRNA conjugate used in the treatment method of McSwiggen et al. to comprise the structure of the conjugate regarding the lipophilic ligand capable of binding albumin, linker comprising a branching molecule attached to the siRNA and a hydrophilic spacer attaching the branching molecule to the lipophilic ligand of Sarett et al. with a reasonable expectation of success. There would be a reasonable expectation of success because McSwiggen et al. suggests the siNA capable of mediating RNAi against MMP13 can be chemically modified and include a conjugate which can be attached to the chemically modified siRNA molecule via a biodegradable linker, and Sarett et al. also pertains to siRNA conjugates, and would amount to simple substitution of one known element for another to obtain predictable results. There would also be a reasonable expectation of success because the final structure of the conjugate shown in the SI Appendix of Sarett et al. is almost identical to that shown in instant Fig. 1B. One of ordinary skill in the art would have been motivated to do so because Sarett et al. taught that clinical translation of therapies based on small interfering RNA (siRNA) is hampered by siRNA’s comprehensively poor pharmacokinetic properties which necessitates molecule modifications and complex delivery strategies but that an siRNA conjugated to a diacyl lipid moiety (siRNA-L2) which rapidly binds albumin in situ exhibited 5.7 fold increase in circulation half-life, 8.6 fold increase in bioavailability and reduced renal accumulation (Abstract). Sarett et al. taught that in situ targeting of albumin following delivery is a viable strategy because endogenous albumin is the most abundant serum protein, and has a circulation half-life of around 20 days, and is a natural carrier of and has high affinity for poorly soluble lipids (page E6491, left column). Sarett et al. taught the strategic choice of modification with an albumin-binding lipid has potential to confer additional advantages in siRNA stability and cell membrane interactions for uptake and endosomal escape in addition to circulation persistence, tissue penetration and bio-distribution (page E6491, left column).
Accordingly, the limitations of claims 1-7,10,11,13-19,21-23,25-30,32 and 35-37 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 9 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over McSwiggen et al. in view of Sarett et al. as applied to claims 1-7,10,11,13-19,21-23,25-30,32 and 35-37 above, and further in view of Brys et al. (US 20120027766, Published 2 Feb 2012).
The teachings of McSwiggen et al. and Sarett et al. as applicable to claims 1-7,10,11,13-19,21-23,25-30,32 and 35-37 have been described above.
McSwiggen et al. and Sarett et al. do not teach the joint associated with the inflammatory disease is a knee, wrist, ankle, shoulder, spinal joint or combination thereof, or how often the conjugate is administered.
Brys et al. teach expression inhibitory agents comprising a polynucleotide selected from antisense and a small interfering siRNA and pharmaceutical compositions thereof useful in treatment of diseases characterized by ECM degradation and/or cartilage degradation such as osteoarthritis (paragraphs 0022-0023). Brys et al. teach elevated expression of MMP-13 in human OA cartilage, and is thought to play an important role in type II collagen degradation in articular cartilage and especially in OA (paragraph 0010). Brys et al. teach osteoarthritis is the most common form of arthritis, and is characterized by the loss of articular cartilage, often associated with hypertrophy of the bone and pain, and mainly affects the hands and weight-bearing joints such as knees, hips, and spines and the process thins the cartilage.
Brys et al. teach long acting pharmaceutical compositions might be administered every 3-4 days, every week, or once every two weeks depending on the half-life and clearance rate of the particular formulation (paragraph 0214).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, that the subject being treated by the method of McSwiggen et al. and Sarett et al. would have increased cartilage protection in a joint associated with osteoarthritis and wherein the joint is a knee or spinal joint based on the teachings of Brys et al. with a reasonable expectation of success. There would be a reasonable expectation of success because Brys et al. also pertains to treating osteoarthritis with siRNAs, and discusses the relation of elevated MMP-13 expression with osteoarthritis. One of ordinary skill in the art would have been motivated to provide the treatment method of McSwiggen et al. and Sarett et al. to a subject having osteoarthritis in a knee or spinal joint because Brys et al. teach siRNA and pharmaceutical compositions thereof useful in treatment of diseases characterized by ECM degradation and/or cartilage degradation such as osteoarthritis (paragraphs 0022-0023), elevated expression of MMP-13 in human OA cartilage, and is thought to play an important role in type II collagen degradation in articular cartilage and especially in OA (paragraph 0010), and that osteoarthritis is the most common form of arthritis, and is characterized by the loss of articular cartilage, often associated with hypertrophy of the bone and pain, and mainly affects the hands and weight-bearing joints such as knees, hips, and spines and the process thins the cartilage.
Accordingly, the limitations of claim 9 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the treatment method of McSwiggen et al. and Sarett et al. regarding the frequency of administration of the conjugate, based on the teachings of Brys et al. One of ordinary skill in the art would have been motivated to do so because Brys et al. teach long acting pharmaceutical compositions might be administered every 3-4 days, every week, or once every two weeks depending on the half-life and clearance rate of the particular formulation (paragraph 0214).
Accordingly, the limitations of claim 12 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 24 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over McSwiggen et al. in view of Sarett et al. as applied to claims 1-7,10,11,13-19,21-23,25-30,32 and 35-37 above, and further in view of Nannuru et al. (WO 2011123394, Published 6 Oct 2011), Hassler et al. (Nucleic Acids Research, 2018 Vol. 46, No. 5, 2185-2196), and Gangopadhyay et al. (RNA Biology, 2022, Vol. 19, No. 1, 452-467).
The teachings of McSwiggen et al. and Sarett et al. as applicable to claims 1-7,10,11,13-19,21-23,25-30,32 and 35-37 have been described above.
McSwiggen et al. and Sarett et al. do not teach the siRNA comprises a nucleotide sequence or the modification pattern of instant SEQ ID NO: 1.
Before the effective filing date, Nannuru et al. taught methods, compounds, compositions for inhibiting expression of MMP-13 mRNA and protein in an animal (Field of invention, page 1). Nannuru et al. taught methods of administering to an animal a therapeutically effective amount of a composition comprising a modified oligonucleotide consisting of 12-30 linked nucleosides and comprising a nucleobase sequence comprising at least 12 contiguous nucleobases of the sequences recited in SEQ ID NOs: 8-85, and a pharmaceutically acceptable carrier (page 19). Nannuru et al. taught the antisense compounds targeted to MMP-13 have chemically modified subunits arranged in patterns, or motifs to confer to the antisense compounds properties such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid or resistance to degradation by in vivo nucleases (page 24). Nannuru et al. taught an antisense oligonucleotide sequence targeting MMP-13 of SEQ ID NO: 16 with 72% inhibition of MMP-13, and which had 5-10-5 MOE wings (Table 4, pages 56-57). See alignment below wherein Qy is instant SEQ ID NO: 1 and Db is SEQ ID NO: 16 of Nannuru et al.:
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Nannuru et al. does not teach the specific chemical modification pattern required by instant SEQ ID NO: 1 shown on page 61 of the instant specification and the Sequence Listing.
Hassler et al. (Nucleic Acids Research, 2018, Vol. 46, No. 5, 2185-2196) teach that siRNA based drugs require chemical modifications or formulation to promote stability, minimize innate immunity, and enable delivery to target tissues, and that most clinically-advanced non-formulated compounds using conjugation as a delivery strategy are fully chemically modified (Abstract). Hassler et al. teach fully modified siRNAs are retained at 100x greater levels in various tissues, independent of the nature of the conjugate or the siRNA sequence and support productive miRNA silencing (Abstract, Introduction, page 2185). Hassler et al. teach GalNAc conjugated siRNAs that are fully modified with alternating 2’-fluoro, 2’-O-methyl pattern, and that recent fine-tuning of the chemical stabilization includes increasing the 2’-O-methyl content, incorporation of additional phosphorothioates, and 5- phosphate stabilization have been shown to further enhance long-term efficacy of conjugated siRNAs (Intro, page 2185).
Hassler et al. teach a fully chemically modified siRNA pattern shown in Figure 1A below which shows a 5’-phosphate at position 1, alternating 2’-O-methyl starting at position 1 and 2’-fluoro RNAs starting at position 2, and phosphorothioate linkages between positions 1 and 2 and 2 and 3 on the 5’ end, and between the last 7 nucleotides on the 3’ end.
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For comparison, the chemical modification pattern for instant SEQ ID NO: 1 which is found on page 61 of the instant specification (and the Sequence Listing) is shown below to aid in comparing the modification pattern.
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Hassler et al. teach testing the fully modified siRNA conjugated to cholesterol in vivo, and that though several configurations were functional, an alternating 2’-O-methyl, 2’–fluoro pattern, with a chemically monophosphorylated, 2’ -O-methyl-modified uridine (U) at position 1, and a 2’-fluoro modified nucleotide at position 14 of the guide strand performed the best (Figure 1A) and that an alternating pattern with a 2’ –fluoro in position 1 of the guide strand reduced silencing activity (data not shown), likely due to placement of 2’-O-methyl groups in positions 2 and 14, which negatively affects potency in the context of heavily modified duplexes. The guide strand was also 5’ -chemically phosphorylated, as terminal 2’-O-methylated U is not a good a substrate for intracellular kinases as natural RNA, and two phosphorothioate linkages to both 5’ and 3’ ends of the passenger and guide strands were added to provide additional resistance to exonucleases (page 2189, left column). Hassler et al. teach the fully modified hsiRNA loaded almost three times more RISC complex compared to the naked siRNA (Figure 1D), which is likely a result of the enhanced stability (page 2189, right column). Hassler et al. also teach that full chemical stabilization significantly enhances conjugate-mediated tissue accumulation independent of the conjugate nature, route of administration and is heavily reliant on the full chemical modification of the siRNA, and also that full chemical stabilization enables productive silencing (Page 2192).
Hassler et al. do not teach that there are only 2 phosphorothioate internucleotide linkages at the 3’ end of the antisense sequence as required by instant SEQ ID NO: 1.
Gangopadhyay et al. (RNA Biology, 2022, Vol. 19, No.1, 452-467) also teach various modifications and modification patterns of siRNA drugs that have been approved by the US FDA (Abstract). Gangopadhyay et al. teach the chemical modification pattern of 3 siRNA FDA approved drugs which are siRNA GalNaC conjugates, shown in Figure 2, which have 2’-O-methyl and 2’-fluoro modifications, as well as 2 phosphorothioate linkages at the last two positions at both the 5’ and 3’ end of the guide strand (antisense strand) (Fig 2 shown below). Gangopadhyay et al. teach replacing phosphodiester linkages with phosphorothioate linkages are explored to design and develop new oligonucleotides with improved RNAi activity, and that phosphorothioate modifications protect siRNA from 3’-exonucleases in vitro and in vivo, placement in the central position in the guide strand inhibits RNAi activity and PS modification increases cellular uptake of siRNAs (pages 461-462).
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Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have used the antisense sequence which targets MMP13 comprising SEQ ID NO: 16 of Nannuru et al. as the antisense sequence of the siRNA used in the treatment method of McSwiggen et al. and Sarett et al., and that the antisense sequence MMP13 comprising SEQ ID NO: 16 of Nannuru et al. would comprise the modification pattern required by instant SEQ ID NO: 1, based on the teachings of Hassler et al. and Gangopadhyay et al. with a reasonable expectation of success. There would be a reasonable expectation of success because McSwiggen et al. suggests the siNA capable of mediating RNAi against MMP13 can be chemically modified and include a conjugate which can be attached to the chemically modified siRNA molecule via a biodegradable linker, and Sarett et al. also pertains to siRNA conjugates, and because Nannuru et al. pertains to antisense sequence targeting the same gene, MMP13 and suggests chemically modified subunits arranged in patterns, or motifs to confer to the antisense compounds properties such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid or resistance to degradation by in vivo nucleases, and Hassler et al. and Gangopadhyay et al. pertain to siRNA conjugates, chemical modifications, patterns and the benefits thereof.
One of ordinary skill in the art would have been motivated to use the antisense sequence which targets MMP13 comprising SEQ ID NO: 16 of Nannuru et al. as the antisense sequence of the siRNA used in the treatment method of McSwiggen et al. and Sarett et al. because Nannuru et al. taught methods of administering to an animal a therapeutically effective amount of a composition comprising a modified oligonucleotide consisting of 12-30 linked nucleosides and comprising a nucleobase sequence comprising at least 12 contiguous nucleobases of the sequences recited in SEQ ID NOs: 8-85, and a pharmaceutically acceptable carrier (page 19) and that the antisense compounds targeted to MMP-13 have chemically modified subunits arranged in patterns, or motifs to confer to the antisense compounds properties such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid or resistance to degradation by in vivo nucleases (page 24) and the antisense oligonucleotide sequence targeting MMP-13 of SEQ ID NO: 16 provided 72% inhibition of MMP-13, and would have amounted to selecting any of the taught MMP-13 sequences that provide MMP-13 inhibition from a list. One of ordinary skill in the art would have been motivated to provide the antisense sequence of SEQ ID NO: 16 of Nannuru et al. with a 5’-phosphate at position 1 on the 5’ end, phosphorothioate linkages at positions 1 and 2 and 2 and 3 of the 5’ end and positions 17 and 18 and 18 and 19 of the 3’ end, and alternating 2’-O-methyl and 2’-F modifications with the 2’-O-methyl starting at position 1 and the 2’-fluoro starting at position 2, because Hassler et al. taught a fully chemically modified siRNA pattern in Figure 1A with a 5’-phosphate at position 1, alternating 2’-O-methyl starting at position 1 and 2’-fluoro RNAs starting at position 2, and phosphorothioate linkages between positions 1 and 2 and 2 and 3 on the 5’ end, and between the last 7 nucleotides on the 3’ end performed the best (Figure 1A), that two phosphorothioate linkages to both 5’ and 3’ ends of the passenger and guide strands were added to provide additional resistance to exonucleases (page 2189, left column), that the fully modified hsiRNA loaded almost three times more RISC complex compared to the naked siRNA (Figure 1D), which is likely a result of the enhanced stability (page 2189, right column), that full chemical stabilization significantly enhances conjugate-mediated tissue accumulation independent of the conjugate nature, route of administration and is heavily reliant on the full chemical modification of the siRNA, and also that full chemical stabilization enables productive silencing (Page 2192). Additionally, Gangopadhyay et al. teach the chemical modification pattern of 3 siRNA FDA approved drugs which are siRNA GalNaC conjugates, shown in Figure 2, which have 2’-O-methyl and 2’-fluoro modifications, as well as 2 phosphorothioate linkages at the last two positions at both the 5’ and 3’ end of the guide strand (antisense strand), and that replacing phosphodiester linkages with phosphorothioate linkages are explored to design and develop new oligonucleotides with improved RNAi activity, and that phosphorothioate modifications protect siRNA from 3’-exonucleases in vitro and in vivo and increases cellular uptake of siRNAs (pages 461-462). In a 19-mer, a total of 4 phosphorothioate linkages would be over 20% phosphorothioate linkages.
Accordingly, the limitations of claims 24 and 38 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 31 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over McSwiggen et al. in view of Sarett et al. as applied to claims 1-7,10,11,13-19,21-23,25-30,32 and 35-37 above, and further in view of Manoharan et al. (U.S. Patent 7,851,615, Issued 14 Dec 2010).
The teachings of McSwiggen et al. and Sarett et al. as applicable to claims 1-7,10,11,13-19,21-23,25-30,32 and 35-37 have been described above.
McSwiggen et al. and Sarett et al. do not teach wherein each lipid includes a C18 hydrocarbon chain.
Before the effective filing date, Manoharan et al. taught iRNA agents attached to a lipophilic moiety (Column 1, lines 5-11). Manoharan et al. taught a wide variety of entities, e.g. ligands, can be tethered to an iRNA agent, and ligands can be coupled directly or indirectly via an intervening tether, to the carrier (Column 11, lines 44-53). Manoharan et al. teach ligands alters the distribution, targeting or lifetime of an iRNA agent into which it is incorporated, and other examples of ligands include lipophilic molecules, including C10,C11,C12,C13,C14,C15,C16,C17,C18,C19 or C20 alkyl (Column 12, lines 4-6,29-32).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date, to have modified the lipophilic ligand comprising a C17 hydrocarbon chain in the conjugate of Sarett et al. used in the treatment method of McSwiggen et al. to be a C18 hydrocarbon chain based on the teachings of Manoharan et al. with a reasonable expectation of success. There would be a reasonable expectation of success because Manoharan et al. pertains to iRNA agents attached to lipophilic moieties and would amount to substituting one known lipophilic ligand with another known lipophilic ligand to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because Manoharan et al. taught a wide variety of entities, e.g. ligands, can be tethered to an iRNA agent and that ligands alter the distribution, targeting or lifetime of an iRNA agent into which it is incorporated, taught multiple examples of ligands include lipophilic molecules, including C10,C11,C12,C13,C14, C15,C16,C17,C18,C19 or C20 alkyl are suitable.
Accordingly, the limitations of claims 31 and 39 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claims 20,31,33,34,38 and 39 are rejected under 35 U.S.C. 103 as being
obvious over McSwiggen et al. in view of Sarett et al. as applied to claims 1-
7,10,11,13-19,21-23,25-30,32 and 35-37 above, and further in view of Duvall et al.
(WO 2023034561, EFD 02 Sept 2021), cited on an IDS.
The applied reference has a common inventor and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
The teachings of McSwiggen et al. and Sarett et al. as applicable to claims 1-7,10,11,13-19,21-23,25-30,32 and 35-37 have been described above.
McSwiggen et al. and Sarett et al. do not teach the hydrophilic blocks of the hydrophilic spacer are attached to each other through phosphorothioate linkages, or wherein each lipid includes a C18 hydrocarbon chain, or each branch of the branching molecule is attached to an individual hydrophilic spacer and each spacer is attached to an individual lipid of the lipophilic ligand; or wherein the hydrophilic spacer is attached to the lipophilic ligand through a phosphorothioate linkage.
Before the effective filing date, Duvall et al. taught conjugates including an oligonucleotide, lipophilic ligand capable of binding albumin, and a linker attaching the oligonucleotide and the lipophilic ligand, the linker comprising a branching molecule attached to the oligonucleotide and a hydrophilic spacer attaching the branching molecule and lipophilic ligand (paragraph 0005). Duvall et al. taught conjugates including an siRNA; a lipophilic ligand capable of binding albumin, the lipophilic ligand including two independent lipids, each lipid including a C18 hydrocarbon chain; and a linker attaching the siRNA and the lipophilic ligand, the linker including a branching molecule attached to the siRNA and including at least one branch point having at least two independent branches, and a hydrophilic spacer attaching an individual branch and an individual lipid, the hydrophilic spacer including 1 to 6 hydrophilic blocks, each hydrophilic block including 2 to 10 repeats of ethylene glycol (paragraph 0006). Duvall et al. taught the oligonucleotide, the linker, and the lipophilic ligand can be attached to each other through various types of linkages/bonds; the oligonucleotide, the linker, and/or the lipophilic ligand can be attached through phosphorothioate bonds (paragraph 0036). Duvall et al. taught the arrangement and composition of the linker can provide the conjugate with advantageous properties, such as, but not limited to, binding to albumin, decreased propensity to self-assembly into micelles, and improved pharmacokinetics (paragraph 0052). Duvall et al. taught each branch of the branching molecule can be attached to an individual hydrophilic spacer. In addition, each hydrophilic spacer can be individually attached to an individual lipid of the lipophilic ligand; In some embodiments, the hydrophilic spacer is attached to the lipophilic ligand, the branching molecule, or both through phosphorothioate bonds (paragraph 0060). Duvall et al. taught the conjugate includes about 20% to about 60 % phosphorothioate linkages based on the total amount of phosphate-based linkages in the conjugate. Duvall et al. taught that proximal positioning of a divalent lipid-siRNA conjugate branching point can improve in vitro and in vivo outcomes (FIG. 6 A) and structures of branching position variants of conjugate investigated (FIG. 6B).
Therefore, it would have been obvious to have modified the hydrophilic spacer, lipid, and branching molecule of the conjugate of Sarett et al. used in the treatment method of McSwiggen et al., based on the teachings of Duvall et al. with a reasonable expectation of success. There would be a reasonable expectation of success, because both Sarett et al. and Duvall et al. pertain to very similar siRNA conjugates with lipophilic ligands and linkers. One of ordinary skill in the art would have been motivated to have modified the hydrophilic spacer, lipid, and branching molecule of the conjugate of Sarett et al. used in the treatment method of McSwiggen et al., with each of the above limitations because Duvall et al. taught that proximal positioning of a divalent lipid-siRNA conjugate branching point can improve in vitro and in vivo outcomes (FIG. 6 A) and structures of branching position variants of conjugate investigated (FIG. 6B) and that the arrangement and composition of the linker can provide the conjugate with advantageous properties, such as, but not limited to, binding to albumin, decreased propensity to self-assembly into micelles, and improved pharmacokinetics (paragraph 0052).
Accordingly, the limitations of claims 20,31,33,34,38 and 39 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-23 and 25-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 and 23-40 of copending Application No. 18/737,720 (‘720) in view of McSwiggen et al. (US 20090099121, Published 16 April 2009).
Claims 1-40 of ‘720 recite a method of treating a central nervous system disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, optionally in combination with a pharmaceutically acceptable excipient, wherein the conjugate comprises a siRNA capable of inhibiting expression of a protein associated with the CNS disease; a lipophilic ligand capable of binding albumin; and a linker attaching the siRNA to the lipophilic ligand, the linker comprising a branching molecule attached to the siRNA, and a hydrophilic spacer attaching the branching molecule to the lipophilic ligand.
Instant claims 1-23 and 25-39 recite a method of treating an inflammatory disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, optionally in combination with a pharmaceutically acceptable excipient, wherein the conjugate comprises a siRNA capable of inhibiting expression of a protein associated with the inflammatory disease and recites the same limitation of the lipophilic ligand and linker. The limitations regarding the structure of the conjugate of the lipophilic ligand and linker are the same in instant claims 1-23 and 25-39.
‘720 does not recite a method of treating an inflammatory disease, or the same routes of administration as in instant claim 2, or that the siRNA hybridizes to an oligonucleotide encoding MMP13.
The teachings of McSwiggen et al. have been described above in the 103 rejection.
It would have been obvious to one of ordinary skill in the art to use the siRNA conjugate comprising the lipophilic ligand and linker of ‘720 in a method of treating an inflammatory disease in a subject in need thereof, and wherein the siRNA is capable of inhibiting expression of MMP13 based on the teachings of McSwiggen et al. There would be a reasonable expectation of success because McSwiggen et al. suggests the siNA capable of mediating RNAi against MMP13 can be chemically modified and include a conjugate which can be attached to the chemically modified siRNA molecule via a biodegradable linker, and would amount to simple substitution of one known element for another to obtain predictable results. One of ordinary skill in the art would have been motivated to use such an siRNA conjugate comprising the structure of the lipophilic ligand and linker of ‘720 and apply to an siRNA that targets other proteins to treat other diseases, such as taught by McSwiggen et al. which teach compounds, compositions, and methods for treatment of diseases and conditions that respond to modulation of matrix metalloproteinase 13 (MMP13) gene expression and/or activity, including short interfering nucleic acid (siNA) and short interfering RNA (siRNA) molecules capable of mediating RNA interference against MMP13 gene expression and are useful for treating diseases and conditions that respond to modulation of MMP13 gene expression in a subject such as inflammatory diseases, disorders or conditions, including rheumatoid arthritis and osteoarthritis (paragraph 0003,0135-0137). McSwiggen et al. teach a composition comprising an siRNA molecule of the invention in a pharmaceutically acceptable carrier or diluent, and a method of treating comprising administering to the subject a composition of the invention (paragraph 0150), and that
the siNA capable of mediating RNAi against MMP13 can be chemically modified and include a conjugate which can be attached to the chemically modified siRNA molecule via a biodegradable linker.
This is a provisional nonstatutory double patenting rejection.
Claims 24 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 22 of copending Application No. 18/737,720 (‘720) in view of McSwiggen et al. (US 20090099121, Published 16 April 2009) as applied to claims 1-23 and 25-39 above and further in view of Nannuru et al. (WO 2011123394, Published 6 Oct 2011), Hassler et al. (Nucleic Acids Research, 2018 Vol. 46, No. 5, 2185-2196), and Gangopadhyay et al. (RNA Biology, 2022, Vol. 19, No. 1, 452-467).
Claim 22 of ‘720 recites the siRNA comprises a nucleotide sequence of SEQ ID NO: 1-17 or a combination thereof.
‘720 does not recite the siRNA comprising the nucleotide sequence of instant SEQ ID NO: 1.
The teachings of Nannuru et al., Hassler et al. and Gangopadhyay et al. have been described in the 103 rejections above.
Therefore, it would have been obvious to swap the siRNA sequences of ‘720 with an siRNA comprising SEQ ID: 16 as the antisense sequence as taught by Nannuru et al. which targets MMP-13 and use in the treatment method of McSwiggen et al., and to provide SEQ ID NO: 16 of Nannuru et al. with the modification pattern required by instant SEQ ID NO: 1, based on the teachings of Hassler et al. and Gangopadhyay et al. with a reasonable expectation of success. There would be a reasonable expectation of success because McSwiggen et al. suggests the siNA capable of mediating RNAi against MMP13 can be chemically modified and include a conjugate which can be attached to the chemically modified siRNA molecule via a biodegradable linker, and because Nannuru et al. pertains to antisense sequence targeting the same gene, MMP13 and suggests chemically modified subunits arranged in patterns, or motifs to confer to the antisense compounds properties such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid or resistance to degradation by in vivo nucleases, and Hassler et al. and Gangopadhyay et al. pertain to siRNA conjugates, chemical modifications, patterns and the benefits thereof.
One of ordinary skill in the art would have been motivated to use the antisense sequence which targets MMP13 comprising SEQ ID NO: 16 of Nannuru et al. as the antisense sequence of the siRNA used in the treatment method of McSwiggen et al. because Nannuru et al. taught methods of administering to an animal a therapeutically effective amount of a composition comprising a modified oligonucleotide consisting of 12-30 linked nucleosides and comprising a nucleobase sequence comprising at least 12 contiguous nucleobases of the sequences recited in SEQ ID NOs: 8-85, and a pharmaceutically acceptable carrier (page 19) and that the antisense compounds targeted to MMP-13 have chemically modified subunits arranged in patterns, or motifs to confer to the antisense compounds properties such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid or resistance to degradation by in vivo nucleases (page 24) and the antisense oligonucleotide sequence targeting MMP-13 of SEQ ID NO: 16 provided 72% inhibition of MMP-13, and would have amounted to selecting any of the taught MMP-13 sequences that provide MMP-13 inhibition from a list. One of ordinary skill in the art would have been motivated to provide the antisense sequence of SEQ ID NO: 16 of Nannuru et al. with a 5’-phosphate at position 1 on the 5’ end, phosphorothioate linkages at positions 1 and 2 and 2 and 3 of the 5’ end and positions 17 and 18 and 18 and 19 of the 3’ end, and alternating 2’-O-methyl and 2’-F modifications with the 2’-O-methyl starting at position 1 and the 2’-fluoro starting at position 2, because Hassler et al. taught a fully chemically modified siRNA pattern in Figure 1A with a 5’-phosphate at position 1, alternating 2’-O-methyl starting at position 1 and 2’-fluoro RNAs starting at position 2, and phosphorothioate linkages between positions 1 and 2 and 2 and 3 on the 5’ end, and between the last 7 nucleotides on the 3’ end performed the best (Figure 1A), that two phosphorothioate linkages to both 5’ and 3’ ends of the passenger and guide strands were added to provide additional resistance to exonucleases (page 2189, left column), that the fully modified hsiRNA loaded almost three times more RISC complex compared to the naked siRNA (Figure 1D), which is likely a result of the enhanced stability (page 2189, right column), that full chemical stabilization significantly enhances conjugate-mediated tissue accumulation independent of the conjugate nature, route of administration and is heavily reliant on the full chemical modification of the siRNA, and also that full chemical stabilization enables productive silencing (Page 2192). Additionally, Gangopadhyay et al. teach the chemical modification pattern of 3 siRNA FDA approved drugs which are siRNA GalNaC conjugates, shown in Figure 2, which have 2’-O-methyl and 2’-fluoro modifications, as well as 2 phosphorothioate linkages at the last two positions at both the 5’ and 3’ end of the guide strand (antisense strand), and that replacing phosphodiester linkages with phosphorothioate linkages are explored to design and develop new oligonucleotides with improved RNAi activity, and that phosphorothioate modifications protect siRNA from 3’-exonucleases in vitro and in vivo and increases cellular uptake of siRNAs (pages 461-462).
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-39 are rejected.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636