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 .
It is noted that the specification discloses: The terms "prevent" or "prevention" as used herein are defined as eliminating or reducing the likelihood of occurrence of one or more symptoms of a disease or disorder. For example, the inhibitor disclosed herein can be used to prevent the occurrence of metabolic and/or vascular diseases.
Specification
The substitute specification filed on 3/4/26 is objected to because there are structures on pages 10, 130, 133, 134, 153, 156, 157, 161-163, 182, 183, 196-202, 208, 209, 211-214, 216, and 217 that are not fully legible. Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-9 and 12-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Montasser et al. (US 2018/0346888 A1), as evidenced by Bressler et al. (Diabetologia (1996) 39: 1345–1350), in view of Salonen et al. (WO 2007/128884 A1), Rossomando et al. (WO 2013/013013 A2), and Avkin-Nachum (WO 2011/066475 A1).
Montasser et al. teach methods of modulating endogenous B4GALT1 genomic, mRNA, and cDNA nucleic acid molecules, and polypeptides, methods of ascertaining the risk of developing cardiovascular conditions by detecting the presence or absence of the variant B4GALT1 genomic, mRNA, and cDNA nucleic acid molecules, and polypeptides, and methods of treating cardiovascular conditions are provided herein (abstract).
Montasser et al. teach: [0007] Cardiovascular disease is the leading cause of death in the United States and other westernized countries. Major risk factors for atherothrombotic cardiovascular diseases such as stroke and myocardial infarction include increased blood cholesterol and thrombotic tendency. Many proteins that are involved in lipid metabolism and coagulation are glycosylated and, thus, subject to modulation by B4GALT1. Knowledge of genetic factors underlying the development and progression of cardiovascular conditions could improve risk stratification and provide the foundation for novel therapeutic strategies.
Montasser et al. teach: [0028] The present disclosure also provides methods of treating a subject that has or is susceptible to developing a cardiovascular condition comprising introducing into the subject an antisense DNA, RNA, an siRNA, or an shRNA that hybridizes to a sequence within the endogenous B4GALT1 gene and decreases expression of B4GALT1 polypeptide in a cell in the subject (instant claim 1).
Montasser et al. teach: [0313] methods in which endogenous B4GALT1 mRNA that is not the variant B4GALT1 is targeted for reduced expression, such as through use of antisense RNA, siRNA, or shRNA.
Montasser et al. teach: [0181] Non-limiting examples of a cardiovascular condition include an elevated level of one or more serum lipids. The serum lipids comprise one or more of cholesterol, LDL, HDL, triglycerides, HDL-cholesterol, and non-HDL cholesterol, or any subfraction thereof (e.g., HDL2, HDL2a, HDL2b, HDL2c, HDL3, HDL3a, HDL3b, HDL3c, HDL3d, LDL1, LDL2, LDL3, lipoprotein A, Lpa1, Lpa1, Lpa3, Lpa4, or Lpa5). A cardiovascular condition may comprise elevated levels of coronary artery calcification. A cardiovascular condition may comprise Type IId glycosylation (CDG-IId). A cardiovascular condition may comprise elevated levels of pericardial fat. A cardiovascular condition may also comprise coronary artery disease (CAD), myocardial infarction (MI), peripheral artery disease (PAD), stroke, pulmonary embolism, deep vein thrombosis (DVT), and bleeding diatheses and coagulopathies. A cardiovascular condition may comprise an atherothrombotic condition. The atherothrombotic condition may comprise elevated levels of fibrinogen. The atherothrombotic condition may comprises a fibrinogen-mediated blood clot. A cardiovascular condition may comprise elevated levels of fibrinogen. A cardiovascular condition may comprise a fibrinogen-mediated blood clot. A cardiovascular condition may comprise a blood clot formed from the involvement of fibrinogen activity. A fibrinogen-mediated blood clot or blood clot formed from the involvement of fibrinogen activity may be in any vein or artery in the body.
Montasser et al. teach: [0329] The present disclosure provides methods of decreasing LDL in a subject in need thereof, by reducing expression of endogenous wild-type B4GALT1 or increasing expression of B4GALT1 Asn352Ser, by any of the methods described herein. The present disclosure provides methods of decreasing total cholesterol in a subject in need thereof, by reducing expression of endogenous wild-type B4GALT1 (instant claim 1).
Montasser et al. teach: [0033] In any of the methods described or exemplified herein, a cardiovascular condition may comprise levels of one or more serum lipids that increase atherosclerotic risk. The serum lipids comprise one or more of cholesterol, LDL, HDL, triglycerides, HDL-cholesterol, and non-HDL cholesterol, or any subfraction thereof (e.g., HDL2, HDL2a, HDL2b, HDL2c, HDL3, HDL3a, HDL3b, HDL3c, HDL3d, LDL1, LDL2, LDL3, lipoprotein A, Lpa1, Lpa1, Lpa3, Lpa4, or Lpa5). A cardiovascular condition may comprise elevated levels of coronary artery calcification. A cardiovascular condition may comprise elevated levels of pericardial fat. A cardiovascular condition may comprise an atherothrombotic condition. The atherothrombotic condition may comprise elevated levels of fibrinogen. The atherothrombotic condition may comprise a fibrinogen-mediated blood clot. A cardiovascular condition may comprise elevated levels of fibrinogen. A cardiovascular condition may comprise a fibrinogen-mediated blood clot. A cardiovascular condition may comprise a blood clot formed from the involvement of fibrinogen activity. A fibrinogen-mediated blood clot or blood clot formed from the involvement of fibrinogen activity may be in any vein or artery in the body.
Montasser et al. teach: [0307] The present disclosure also provides therapeutic methods and methods of treatment or prophylaxis of a cardiovascular condition in a subject having or at risk of having the disease using the methods disclosed herein for modifying or altering expression of an endogenous B4GALT1 gene. The present disclosure also provides therapeutic methods and methods of treatment or prophylaxis of a cardiovascular condition in a subject having or at risk for the disease using methods for decreasing expression of endogenous B4GALT1 mRNA or using methods for providing recombinant nucleic acids encoding B4GALT1 polypeptides, providing mRNAs encoding B4GALT1 polypeptides, or providing B4GALT1 polypeptides to the subject. The methods can comprise introducing one or more nucleic acid molecules or proteins into the subject, into an organ of the subject, or into a cell of the subject (e.g., in vivo or ex vivo).
Therefore, Montasser et al. teach a method of treating a vascular disease associated with elevated cholesterol, more specifically cardiovascular disease including coronary artery disease, via delivering a siRNA that hybridizes to a sequence within the endogenous B4GALT1 gene and decreases expression of B4GALT1 polypeptide in a cell in the subject (instant claim 1). Montasser et al. teach that the subject is human (instant claim 8).
Montasser et al. teach that the method can be used for various cardiovascular conditions including, but not limited to, elevated levels of serum lipids, and elevated levels fibrinogen, coronary artery calcification, coronary artery disease (CAD), and increased levels of aspartate aminotransferase (AST) [0064].
Coronary artery disease, as taught by Montasser et al., meets the instant limitation of being associated with insulin resistance, as evidenced by Bressler et al. Bressler et al. teaches that the magnitude of insulin resistance is positively correlated with the severity of coronary artery disease (page 1345) (instant claim 2).
Instant claims 3, 6, and 9 recite an outcome instead of a method step and therefore necessarily flow from the recited method step.
Montasser et al. teach: [0109] The disclosed nucleic acid molecules can be made up of, for example, nucleotides or non-natural or modified nucleotides, such as nucleotide analogs or nucleotide substitutes. Such nucleotides include a nucleotide that contains a modified base, sugar, or phosphate group, or that incorporates a non-natural moiety in its structure. Examples of non-natural nucleotides include, but are not limited to, dideoxynucleotides, biotinylated, aminated, deaminated, alkylated, benzylated, and flourophore-labeled nucleotides (instant claim 17).
Montasser et al. teach: [0111] Nucleotide analogs can also include modifications of the sugar moiety. Modifications to the sugar moiety include, but are not limited to, natural modifications of the ribose and deoxy ribose as well as synthetic modifications. Sugar modifications include, but are not limited to, the following modifications at the 2′ position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl (instant claim 18).
Montasser et al. teach: [0110] The nucleic acid molecules disclosed herein can also comprise one or more nucleotide analogs or substitutions. A nucleotide analog is a nucleotide which contains a modification to either the base, sugar, or phosphate moieties. Modifications to the base moiety include, but are not limited to, natural and synthetic modifications of A, C, G, and T/U, as well as different purine or pyrimidine bases. Often, base modifications can be combined with, for example, a sugar modification, such as 2′-O-methoxyethyl, to achieve unique properties such as increased duplex stability (instant claim 19).
Montasser et al. teach: Pharmaceutical compositions can be formulated using one or more physiologically and pharmaceutically acceptable carriers, diluents, excipients or auxiliaries [0327] (instant claim 20).
Montasser et al. does not teach attachment of the siRNA to a ligand, more specifically a GalNAc ligand (instant claims 1 and 12).
However, it was known in the art to attach siRNAs to GalNAc, as evidenced by Rossomando et al. Rossomando et al. teach siRNAs with improved pharmacokinetic properties with incorporation of a GalNAc ligand (abstract and [0007]). It would have been obvious to incorporate the GalNAc ligand into the siRNA of Montasser et al. with an expectation of successful delivery and improved pharmacokinetic properties. It would have been obvious to conjugate the ligand to the 5’ or 3’ end as a matter of design choice (i.e. Figure 1) (instant claim 21).
Montasser et al. teach that the compound is a siRNA, which is known in the field to be in a specific size range, but does not explicitly teach that the siRNA has a length from 15-30 or 19-25 nucleotides; or wherein the first strand has a length of 23 nucleotides and the second strand has a length of 21 nucleotides (instant claims 13-15).
However, Rossomando et al. teach: [00165] The RNA effector molecule is a double-stranded oligonucleotide. Typically, the duplex region formed by the two strands is small, about 30 nucleotides or less in length. Such dsRNA is also referred to as siRNA. For example, the siRNA may be from 15 to 30 nucleotides in length, from 10 to 26 nucleotides in length, from 17 to 28 nucleotides in length, from 18 to 25 nucleotides in length, or from 19 to 24 nucleotides in length, etc. It is noted that instant claim 15 does not require for each strand to be a different length, but rather require for the first strand to comprise a length of 23 nucleotides and the second strand to comprise a length of 21 nucleotides, both of which fall into the size ranges taught by Rossomando et al.
Rossomando et al. teach: [00161] Complementary sequences within a RNA effector molecule, e.g., within a dsRNA (a double-stranded ribonucleic acid) may be fully complementary or substantially complementary. Generally, for a duplex up to 30 base pairs, the dsRNA comprises no more than 5, 4, 3 or 2 mismatched base pairs upon hybridization, while retaining the ability to regulate the expression of its target gene.
Montasser et al. does not teach incorporation of terminal inverted abasic nucleosides (instant claim 16).
However, Avkin-Nachum teaches terminal modifications of siRNAs and teaches that the terminal modification can be inverted abasic moieties. Avkin-Nachum teaches that such modifications are incorporated, for example at the 3' terminus of the sense and/or antisense strands. Avkin-Nachum teaches that the modifications are utilized for capping (page 13). It would have been obvious to incorporate this modification into the siRNA of Montasser with the expectation of the protective benefits taught by Avkin-Nachum (instant claim 22).
With regards to obesity (instant claims 4-7), Salonen et al. teaches that B4GALT1 is an obesity risk gene (Table 1). Since Montasser et al. teach that the method can be used for various cardiovascular conditions including, but not limited to, elevated levels of serum lipids, one would expect that a decrease in levels of serum lipids would benefit treating or managing a symptom of obesity or weight gain. Additionally, Montasser et al. teach that inhibition of B4GALT1 resulted in a decrease in cholesterol levels, which meet the instant limitation of “managing” obesity or weight gain.
Salonen et al. teaches utilizing a sequence specific gene silencing agent, more specifically a siRNA, to modulate the biological activity or function of an obesity associated gene including B4GALT1 in a mammalian subject and a method of treating obesity with the siRNA (claims 56, 64, 68, and 76).
Response to Arguments
Applicant argues that while Montasser mentions siRNA as a potential modality for knocking down B4GALT1, it does not teach or suggest any specific siRNA oligonucleotide sequences, and provides only high-level guidance regarding the targeting of B4GALT1 mRNA. Applicant is arguing limitations that are not claimed. The instant claims are not directed to any specific siRNA. Montasser et al. is not required to disclose any specific siRNA.
Applicant argues that the only data that Montasser shows relating to B4GALT1 inhibition is knockdown of B4GALT1 expression in zebrafish larvae using morpholino oligonucleotides, not siRNA. Morpholinos function via steric blocking of mRNA, i.e., by physically obstructing translation. In contrast, siRNA inhibition occurs via a fundamentally different biological pathway and mechanism, involving the catalytic RISC pathway in which the targeted mRNA is tagged for enzymatic degradation. One of skill in the art would therefore not expect for morpholino knockdown results obtained in zebrafish larvae to be generalizable to results in humans, much less that siRNA-ligand conjugate-mediated inhibition of B4GALT1 in humans would provide a similar effect to morpholino inhibition in zebrafish larvae. Further, Montasser does not teach that B4GALT1 knockdown is a clinically safe method of treatment. Montasser's own results points to a partial-loss (i.e., hypomorphic) protective state of B4GALT1 from the N352S variant, rather than a complete loss of B4GALT1, which is reported to have ~50% decreased enzymatic activity. Montasser further discloses that complete inactivation of B4GALT1 is associated with B4GALT1-CDG, a devastating disease characterized by hydrocephalus, life-threatening bleeding, and intellectual disability, see Example 10, paragraph [0390]. Therefore, one of skill in the art would not equate a general teaching to decrease expression of B4GALT1, without a clearly defined therapeutic window of how much inhibition is safe, with a clear, clinically actionable teaching, especially for a potent treatment modality such as an siRNA-ligand conjugate. One of skill in the art reading Montasser would have no expectation that knockdown of B4GALT1 would lead to a beneficial effect as claimed, and would in fact expect that significant knockdown of mRNA levels (e.g., beyond 50%) could be associated with poor clinical outcomes.
Contrary to applicant’s arguments, Montasser et al. is not required to provide siRNA data. Montasser et al. clearly teach a method of inhibition of B4GALT1 for the treatment of a cardiovascular disease meeting the instant limitations and clearly teach that the inhibitor can be a B4GALT1 siRNA.
Montasser et al. teach: [0028] The present disclosure also provides methods of treating a subject that has or is susceptible to developing a cardiovascular condition comprising introducing into the subject an antisense DNA, RNA, an siRNA, or an shRNA that hybridizes to a sequence within the endogenous B4GALT1 gene and decreases expression of B4GALT1 polypeptide in a cell in the subject.
Montasser et al. teach: [0313] methods in which endogenous B4GALT1 mRNA that is not the variant B4GALT1 is targeted for reduced expression, such as through use of antisense RNA, siRNA, or shRNA.
Montasser et al. teaches using CRISPR technology for editing a mutation and differentiates that siRNAs are used for reducing the expression of endogenous B4GALT1 mRNA for treatment of a cardiovascular disease. It would be routine in the art for one of ordinary skill in the art to determine therapeutic parameters, none of which are instantly claimed.
Applicant argues that Rossomando discloses compositions and methods for producing various modified glycoproteins, yet is completely silent regarding targeting B4GALT1. Rossomando is not relied upon for targeting B4GALT1. Applicant argues that Rossomando discusses GalNAc modifications only briefly in paragraph [0007] as possible modifications at serine or threonine residues. Nothing in Rossomando would lead one of skill in the art to select a GalNAc ligand out of any possible glycoprotein modification for the purpose of targeting B4GALT1 mRNA with an siRNA-ligand conjugate.
Rossomando et al. teach siRNAs with improved pharmacokinetic properties with incorporation of a GalNAc ligand and therefore it would have been an obvious structural element for conjugation to any siRNA. Applicant is arguing that Rossomando et al. does not teach every element, although the reference was not relied upon for every element. It is the combination of references that render the claims obvious in a rejection under 35 USC 103(a).
Applicant argues that Avkin-Nachum discloses double-stranded siRNA constructs comprising modified terminal ribonucleotides. However, Avkin-Nachum does not teach or suggest the siRNA-ligand conjugates of the claimed methods, much less using double-stranded siRNAs for targeting B4GALT1 to inhibit its expression and treat cardiovascular disease, obesity, or a metabolic syndrome. Applicant is arguing that Avkin-Nachum et al. does not teach every element, although the reference was not relied upon for every element. It is the combination of references that render the claims obvious in a rejection under 35 USC 103(a).
Applicant argues that Salonen discloses that B4GALT1 is a risk gene for obesity based on a genomic analysis of individuals with type 2 diabetes. Salonen does not teach or suggest any association between circulating B4GALT1 mRNA expression levels and insulin resistance, elevated blood levels of free fatty acids, elevated blood levels of total cholesterol, elevated blood levels of triglycerides, or diabetes, much less that the claimed methods of administering an siRNA-ligand conjugate targeting B4GALT1 would be effective for preventing, treating, or managing a cardiovascular disease, obesity, weight gain, or metabolic syndrome associated with any of same. Applicant is arguing that Salonen et al. does not teach every element, although the reference was not relied upon for every element. It is the combination of references that render the claims obvious in a rejection under 35 USC 103(a). With regards to circulating B4GALT1 mRNA expression levels and insulin resistance, Salonen et al. teaches utilizing a sequence specific gene silencing agent, more specifically a siRNA, to modulate the biological activity or function of an obesity associated gene including B4GALT1 in a mammalian subject and a method of treating obesity with the siRNA (claims 56, 64, 68, and 76).
Applicant argues that FIGs. 8, 9, and 11 of the present application show evidence of effective knockdown of B4GALT1 mRNA levels, with relative B4GALT1 expression levels falling below about 50% for all constructs tested, indicating a strong inhibitory effect. Again, the instant claims are not directed to any specific siRNA. Given the teachings of the prior art, it would have been obvious to utilize a siRNA targeting B4GALT1 to treat a cardiovascular disease; and it was routine in the art to screen for active siRNAs to a given target. The instant claims are directed to delivery of any siRNA targeting B4GALT1. Certainly species within this genus would be obvious given the teachings of Montasser et al. regarding delivery of siRNAs to inhibit B4GALT1.
Applicant argues that FIGs. 10, and 12-16 further provide evidence that administration of siRNA-ligand conjugates in mice leads to significant reductions in body weight, cholesterol, fibrinogen, free fatty acids, and insulin resistance. These surprising effects on a variety of parameters relating to cardiovascular health are unexpected because of the magnitude of the effects across parameters and tissues. These data provide strong evidence of non-obviousness. Contrary to applicant’s arguments, it is not surprising for inhibition of B4GALT1 to treat a cardiovascular disease, as taught by Montasser et al. The claims are not directed to delivery of any specific compound in any specific delivery composition to treat any specific condition that applicant has demonstrated as unexpected.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636