The office action mailed on 10/7/26 has been vacated.
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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/21/26 has been entered.
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 9/21/26 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.
Response to Arguments
Applicant argues that the Substitute Specification submitted herewith has been amended to provide higher-resolution versions of the structures on pages 10, 130, 133, 134, 153, 156, 157, 161-163, 182, 183, 196-202, 208, 209, 211-214, 216, and 217 of the Substitute Specification filed on March 4, 2026. The structures in the Substitute Specification are fully legible and of the best quality available.
Applicant further respectfully submits that Scheme 4 has been replaced with a corrected, higher-resolution version of Scheme 4 appearing in International Application No. PCT/EP2024/071312, of which the present application is a bypass continuation application. The replacement of Scheme 4 does not introduce new matter beyond the disclosure of International Application No. PCT/EP2024/071312, to which the present application claims priority benefit; this replacement instead conforms Scheme 4 to that disclosure and addresses the quality of the structure.
The structures in the specification are still not fully legible.
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) 1-7, 9, and 12-23 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), Zhang (US 2022/0054645 A1), Avkin-Nachum (WO 2011/066475 A1), and Apovian et al. (J Clin Endocrinol Metab, February 2015, 100(2):342–362).
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: [0310] Subjects include human and other mammalian subjects (e.g., feline, canine, rodent, mouse, or rat) (instant claim 1).
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).
Montasser et al. teach: [0311] 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 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.
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 1).
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 or increasing expression of B4GALT1 Asn352Ser, by any of the methods described herein.
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 Zhang. Zhang teaches siRNAs conjugated to the 3’ end of the sense strand, wherein each strand is 25 nucleotides in length with resultant targeted delivery of the siRNA to hepatocytes (Figure 2). 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 targeted delivery (instant claims 12-15 and 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, Zhang teaches siRNAs conjugated to the 3’ end of the sense strand, wherein each strand is 25 nucleotides in length with resultant targeted delivery of the siRNA to hepatocytes (Figure 2). Zhang teaches: [0040] In still another aspect, the oligonucleotide is an siRNA. Preferably, the siRNA is between 10-27 nucleotides in length. Most preferably, it is between 19-25 nucleotides in length. Preferably, the targeting ligand is GalNAc.
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 and 23), Montasser et al. demonstrates that decreased B4GALT1 is associated with decreased circulating LDL-C. Because LDL-C contributes to total cholesterol, the cardiovascular disease is associated with elevated total cholesterol and Apovian et al. teaches that dyslipidemia is a recognized obesity-associated comorbidity and that its management is an important component of medical care for patients with obesity. One of ordinary skill in the art would have been motivated to administer the B4GALT1 siRNA as taught by Montasser et al. to manage cholesterol abnormalities associated with obesity. Montasser et al. expressly teaches that the method is used for lowering total cholesterol.
Apovian et al. teaches (recommendation 1.2) dyslipidemia as an obesity-associated comorbidity and discusses ameliorating comorbidities as a part of obesity management.
Apovian (recommendation 1.1) addresses pharmacological approaches for managing obesity including and the clinical rationale for managing dyslipidemia in patients with obesity.
The instant specification discloses: [0154] The terms “manage” or “management” are used herein in their conventional sense to mean that the symptoms associated with the condition afflicting the subject are at least kept under control (i.e., magnitude of the symptom are kept within a predetermined level), where in some instances the symptoms are ameliorated without eliminating the underlying condition.
Additionally, Salonen et al. teaches that B4GALT1 is an obesity risk gene (Table 1). Salonen et al. is evidence that B4GALT1 was already recognized as a potential target associated with obesity and metabolic disease. 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 they have submitted Exhibit A, a publication from the same inventors of Montasser, as further evidence of the state of unpredictability in the art at the time of filing the subject application.
Applicant argues: The Examiner considers that Montasser "provides methods of decreasing total cholesterol in a subject in need thereof, by reducing expression of endogenous wild-type B4GALT1". The Applicant respectfully disagrees and, as will be shown in detail below, Exhibit A demonstrates that the claimed method for targeting B4GALT1 for the treatment of cardiovascular disease associated with total cholesterol is inventive due to at least a lack of expectation that B4GALT1 targeting would reduce total cholesterol levels.
It is noted that that a subsequent publication from the same author expressing different teachings does not, by itself, establish that the earlier patient publication failed to provide a reasonable expectation of success. The reference of the rejection must be evaluated based on what it actually teaches. The later article must be evaluated for whether it provides evidence relevant to the state of the art at the relevant time. The presence of a common author does not necessarily make the later article controlling over the earlier disclosure.
Applicant argues that Exhibit A presents data from both mouse models and a rare human founder population, which, in some aspects, directly contradicts any predictable link between B4GALT1 modulation and the treatment of cardiovascular disease (CAD) associated with total cholesterol:
" In the knock-in mouse model, "no significant differences were observed in total
cholesterol, ApoB-100, HDL-C, triglycerides, or non-esterified fatty acids" when
using B4GALT1 modulation. See page 5 of Exhibit A.
" Similarly, in the adult liver-directed CRISPR model, no significant differences were observed in total cholesterol or HDL-C when using B4GALT1 modulation.
" In addition, the CAD finding in the human study relating to single-variant association arose from a separate B4GALT1 rare-variant burden analysis rather than direct testing of p.Asn352Ser, because direct p.Asn352Ser-CAD testing was not feasible. Taken together, these teachings provide no reasonable basis for predicting that B4GALT1 inhibition by siRNA would treat diseases associated with elevated levels of total cholesterol with any expectation of success.
It is noted that applicant’s arguments are specific to the relationship between B4GALT1 and total cholesterol. The claims are directed to a method of preventing, treating, and/or managing any cardiovascular disease, obesity, or metabolic syndrome that is associated with insulin resistance, elevated blood levels of free fatty acids, elevated blood levels of total cholesterol, elevated blood levels of triglycerides, and/or diabetes. The claims do not require for the method to lower total cholesterol, but rather for the cardiovascular disease, obesity, or metabolic syndrome to have any possible association with insulin resistance, elevated blood levels of free fatty acids, elevated blood levels of total cholesterol, elevated blood levels of triglycerides, and/or diabetes.
Clearly the teachings of Exhibit A are evidence that there is an association to total cholesterol and teaches that B4galt1 knockdown in liver of adult mice decreases circulating LDL-C levels (page 5 of 7).
Applicant argues that Montasser's only in vivo B4GALT1 knockdown data showing cardiovascular-relevant effects come from morpholino-mediated translational blocking in zebrafish larvae, whereas Exhibit A's knockdown experiments used CRISPR-Cas9 gene editing in mice, thereby resulting in mosaic, permanent DNA editing of B4GALT1, rather than reversible siRNA- mediated mRNA suppression. In contrast, the methods of the pending claims employ a double-stranded siRNA oligomer conjugated to one or more ligand moieties in mammalian patients. Neither morpholino data from zebrafish (Montasser) nor CRISPR editing data from mice (Exhibit A) provide a reasonable basis to predict the therapeutic effects of a double-stranded siRNA oligomer conjugated to one or more ligand moieties in a mammalian patient.
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 the amended claims are directed to methods of administering, to a mammalian patient, a double-stranded siRNA oligomer complementary to B4GALT1 mRNA and conjugated to one or more ligand moieties, for the prevention, treatment, or management of cardiovascular disease, obesity, or metabolic syndrome associated with insulin resistance, elevated blood levels of free fatty acids, elevated blood levels of total cholesterol, elevated blood levels of triglycerides, and/or diabetes (e.g., amended independent claim 1), or obesity, body weight gain, and/or a metabolic syndrome (e.g., amended independent claim 4). None of the cited references, alone or in combination, teaches or suggests these methods or provides a reasonable expectation of success.
The deficiencies of Montasser are discussed above. Montasser is further silent regarding insulin resistance, obesity, and metabolic syndromes, and does not teach a double-stranded siRNA conjugated to one or more ligand moieties for in vivo therapeutic administration in a mammalian patient. Applicant is not required to teach every species recited. Montasser et al. teaches that the inhibitory compound can be a siRNA and 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).
Applicant argues that Montasser (in view of Exhibit A) fails to establish any reasonable expectation that B4GALT1 inhibition would treat cardiovascular disease associated with elevated total cholesterol. The deficiencies of Montasser are not remedied by Bressler as Bressler is silent with regard to B4GALT1. The rejection is not based upon Montasser in view of Exhibit A. The condition taught by Montasser et al. (coronary artery disease) meets the instant limitation of being associated with insulin resistance because 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). Bressler was not relied upon for teaching B4GALT1.
Applicant argues that Montasser (in view of Exhibit A), as described above, does not provide a reasonable expectation that knockdown of B4GALT1 in a patient with cardiovascular disease associated with total cholesterol would improve the clinical outcome. Exhibit A explicitly teaches: Our findings suggest that targeted modulation of protein galactosylation may represent a therapeutic approach to decreasing cardiovascular disease (abstract). Exhibit A specifically identifies B4GALT1 as a target for modulating protein galactosylation to reduce LDL cholesterol and potentially cardiovascular disease. The cardiovascular disease meets the instant limitation of being “associated” with elevated levels of total cholesterol (Exhibit A tests for total cholesterol and the claims do not require for the total cholesterol to be lowered by the method) and with insulin resistance, as evidenced by Bressler et al.
Additionally, as argued by applicant, Montasser et al. and Exhibit A do not utilize the same methods (antisense vs CRISPR) and Montasser et al. teach that siRNA can be used. Therefore, Exhibit A results regarding total cholesterol with CRISPR targeting of a B4GALT1 missense variant may not be equivalent to siRNA results. Montasser et al. offers strong motivation to use a siRNA as the inhibitor and is not required to exemplify such.
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
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).
It is noted that the instant genus of conditions is very broad with any cardiovascular disease, obesity, or metabolic syndrome with any possible association to any of the recited factors.
Montasser et al. clearly teaches delivering siRNA targeted to B4GALT1 for cardiovascular conditions involving serum lipid abnormalities, including cholesterol and triglycerides.
Applicant argues each reference individually for teaching what was not relied upon in that reference. The instant rejection is a rejection under 35 USC 103 rather than 102 and therefore it is the combination of references that render the claims obvious. A reduction in LDL is a portion of total cholesterol.
Regarding obesity, Montasser et al. demonstrates that decreased B4GALT1 is associated with decreased circulating LDL-C. Because LDL-C contributes to total cholesterol, the cardiovascular disease is associated with elevated total cholesterol and Apovian et al. teaches that dyslipidemia is a recognized obesity-associated comorbidity and that its management is an important component of medical care for patients with obesity. One of ordinary skill in the art would have been motivated to administer the B4GALT1 siRNA as taught by Montasser et al. to manage cholesterol abnormalities associated with obesity. Montasser et al. expressly teaches that the method is used for lowering total cholesterol.
The instant specification discloses: [0154] The terms “manage” or “management” are used herein in their conventional sense to mean that the symptoms associated with the condition afflicting the subject are at least kept under control (i.e., magnitude of the symptom are kept within a predetermined level), where in some instances the symptoms are ameliorated without eliminating the underlying condition.
Applicant argues that Salonen identifies 644 different genes associated with obesity. Critically, B4GALT1 appears as a single entry within that list, with no functional data and no indication of whether B4GALT1 is causative or protective in the context of obesity. The number of genes disclosed by Salonen is irrelevant. Salonen et al. teaches that B4GALT1 is an obesity risk gene (Table 1). Salonen et al. is evidence that B4GALT1 was already recognized as a potential target associated with obesity and metabolic disease.
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 Avkin-Nachum discloses general modifications for siRNAs, but does not provide any teaching or suggestion that such modifications would be effective within a double-stranded siRNA oligomer conjugated to one or more ligand moieties targeting B4GALT1 in a mammalian patient. As set forth above, the instant rejection is a rejection under 35 USC 103 rather than 102 and therefore the combination of references render the claims obvious. Avkin-Nachum is not relied upon for teachings of B4GALT1. Certainly types of modifications are not limited to a given target and are universally incorporated into siRNAs specific for different targets.
Applicant argues that the Examples in the as-filed application represent, to Applicant's knowledge, the first published data showing the unexpected finding that a double-stranded siRNA oligonucleotide conjugated to one or more ligand moieties for inhibiting B4GALT1 has wide-ranging effects on insulin resistance (FIG. 16), elevated blood levels of free fatty acids (FIG. 14), elevated blood levels of total cholesterol (FIG. 13A), elevated blood levels of triglycerides (FIG. 13C), and glycemic measures relevant to diabetes, including fasting glucose, HbAlc, and glucose tolerance (FIG. 16). The results argued by applicant are not commensurate in scope with the instant claims which are directed to preventing, treating, and/or managing cardiovascular disease, obesity, or a metabolic syndrome in a patient, the method comprising administering any siRNA nucleic acid inhibitor of expression of Beta-1,4-galactosyltransferase-1 (B4GALT1) that is conjugated to a ligand wherein the cardiovascular disease, obesity, or metabolic syndrome has any possible association with insulin resistance, elevated blood levels of free fatty acids, elevated blood levels of total cholesterol, elevated blood levels of triglycerides, and/or diabetes.
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.
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
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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