DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 35-54 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Mullick et al (WO 2012/149495, November 2012, filed on 27 April 2012, cited from IDS).
Concerning claims 35, 43-45, 53-54 Mullick et al teach a method of treating, preventing or ameliorating of cardiovascular disease such as familial chylomicronemia (FCS) in an animal by administering a compound inhibiting ApoCIII in an animal (see lines 21-25 on page 6, lines 6-8 on page 4, lines 7-10 on page 15, lines 17-20 on page 32). Such a compound can be an antisense compound comprising modified oligonucleotide consisting of 12 to 30 linked nucleosides, which is complementary to ApoCIII nucleic acid of SEQ ID NO: 1, which is fully identical to instant SEQ ID NO: 1 (see lines 4-14 on page 7). Antisense compound can be modified so that it comprises gap segment consisting of 10 linked deoxynucleosides, a 5' wing segment consisting of 5 linked nucleosides; a 3' wing segment consisting of 5 linked nucleosides; wherein the gap segment is positioned immediately adjacent to and between the 5' wing segment and the 3' wing segment and wherein each nucleoside of each wing segment comprises a 2'-O-methyoxyethyl sugar, wherein each cytosine is a 5'-methylcytosine, and wherein each internucleoside linkage is a phosphorothioate linkage (see lines 25-31 on page 7). Such antisense compound can be of SEQ ID NO: 3, which is 100% identical to instant SEQ ID NO: 3 and can be modified with 5-10-5 MOE gapmer motif, same as claimed in instant claims 35 and 45 (see lines 23-25 on page 7, lines 2-3 on page 32, lines 1-3 on page 71). Mullick teach that inhibition of ApoCIII expression unexpectedly results in increased chylomicron clearance and is therefore important in the prevention of chylomicronemia (see lines 10-13 on page 6). Severe forms of chylomicronemia can lead to pancreatitis, a life-threatening condition (see lines 13-14 on page 6). The risk of pancreatitis is considered clinically significant if level of triglyceride-rich lipoproteins such as chylomicrons exceeds 880 mg/dL (see lines 9-17 on page 4). "Wherein" clauses of claims 35, 43-44 and 45, 53-54 are expected to happen upon executing the method in the absence of evidence to the contrary. Concerning claims 36-37 and 46-47 the compound can be administered parenterally or subcutaneously (see lines 1-2 on page 33). Concerning claims 38- 39 and 48-49 the compound can be in salt form such as sodium or potassium salt (see lines 20-21 on page 56) or further comprise pharmaceutically acceptable carrier or diluent (see lines 8-9 on page 33). Concerning claims 40-42 and 50-52 a second therapeutic agent can be used for disease treatment such as cholesterol lowering agent (see lines 3-7 on page 33) or dietary fat restriction (see lines 23-27 on page 26, lines 8-17 on page 67).
Mullick et al do not explicitly teach the step of identifying a patient with FCS and triglyceride level more than 880 mg/dL.
It would have been obvious to one of ordinary skill in the art at the time of the invention to identify a patient with FCS and triglyceride level more than 880 mg/dL and treat such patient with a compound of instant SEQ ID NO: 3 based on teachings of Mullick et al. One of the ordinary skill in the art would be motivated to do so, because Mullick et al teach that the level of triglycerides of 880 mg/dL can cause life-threatening condition of pancreatitis, motivating one of the art to identify such patients and treat them with the compound of SEQ ID NO: 3, which decreases amount of chylomicrons and triglycerides, alleviating the condition and preventing life-threatening pancreatitis.
Claims 35-54 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Crooke et al (US 2004/0208856, October 2004, cited from IDS) and in further view of Sugandhan et al (Pediatric Dermatology, 2007, Vol. 24, No. 3, p. 323-325, cited from IDS), Zheng et al (Circulation, 2010, 121, 15: 1722-1734, cited from IDS) and Mullick et al, above.
Crooke et al teach methods for modulating expression of Apolipoprotein C-III (ApoCIII) (see paragraph [0001]) using inhibitors of ApoCIII (see paragraph [0061]) such as antisense oligonucleotides, which can be single-stranded (see paragraph [0022]). One of the oligonucleotides presented in Table 1, page 22, is of SEQ ID NO: 87, which is 100% identical to instant SEQ ID NO: 3 and shown to be effective in ApoCIII inhibition (see paragraph [0219]). Crooke et al further teach that such antisense oligonucleotide is a gapmer 20 nucleotides in length, composed of a central "gap" region consisting of ten 2'- deoxynucleotides, which is flanked on both sides (5' and 3' directions) by five-nucleotide "wings", which are composed of 2'-methoxyethyl nucleotides and the internucleoside linkages are phosphorothioate throughout the oligonucleotide (see paragraph [0218], Table 1) and cytosine can be modified with 5- methylcytosine (see paragraph [0080]). The oligonucleotide can be parenterally subcutaneously administered (see paragraph [0094]), can be in a salt form (see paragraph [0093]) and can further comprise a pharmaceutically acceptable carrier (see paragraph [0095)). The oligonucleotide can be administered sequentially with a second agent (see paragraph [0108]). Crooke et al teach that ApoCIII slows the clearance of triglyceride-rich lipoproteins by inhibiting lipolysis, both through inhibition of lipoprotein lipase and by interfering with lipoprotein binding to the cell-surface glycosaminoglycan matrix (see paragraph [0004]). Further Crooke et al teach that statin drugs lower triglyceride level (see paragraph [0009]).
Crooke et al do not teach using antisense oligonucleotides against ApoCIII for Familial chylomicronemia syndrome treatment or further treatments with statins or dietary fat restriction, and step of identifying a patient with FCS and triglyceride level more than 880 mg/dL.
Sugandhan et al teach that there are three causes of Familial chylomicronemia syndrome: deficiency of lipoprotein lipase or apolipoprotein CII or the presence of inhibitors of lipoprotein lipase (see Abstract). One of the symptoms of the disease is elevation of triglycerides and chylomicrons (see Abstract). One of the treatments for the disease can be dietary fat restriction (see top of second column on page 324).
Zheng et al teach that patient with hypertriglyceridemia have higher level of Apolipoprotein C-III (ApoCIII) characterized by reduced clearance of triglyceride-rich lipoproteins compared to healthy subjects (see Abstract).
Teachings of Mullick are discussed above.
It would have been obvious to one of ordinary skill in the art at the time of the invention to identify a patient with FCS and triglyceride level more than 880 mg/dL and treat them by using antisense oligonucleotides against ApoCIII according to teachings of Crooke et al, Sugandhan et al, Zheng et al and Mullick et al. One of the ordinary skill in the art would be motivated to do so, because of Sugandhan et al teaching that Familial chylomicronemia syndrome is characterized by increased level of triglycerides and Zheng et al teaching that ApoCIII level is increased in patients with hypertriglyceridemia, therefore inhibiting ApoCIll, which prevents clearance of triglycerides according to Zheng, is going to reduce or treat the disease. One of the ordinary skill in the art would be motivated to use antisense oligonucleotides taught by Crooke et al, because they were shown to effectively inhibit ApoCIII. One of the ordinary skill in the art would be motivated to identify patients with the level of triglycerides of 880 mg/dL, because Mullick et al teach that that level of triglycerides can cause life-threatening condition of pancreatitis, motivating one of the art to identify such patients and treat them. Further one of the ordinary skill in the art would be motivated to use antisense oligonucleotides taught by Crooke et al in combination with statins, because Crooke et al teach that statins reduce level of ApoCIll, same as antisense compounds of Crooke et al, therefore both are directed to the same target, inhibiting ApoCIII. Further one of the ordinary skill in the art would be motivated to use dietary fat restriction in combination with antisense compounds of Crooke et al, because Sugandhan et al teach that dietary fat restriction is another way of the same disease treatment. "Wherein" clauses of claims 35, 43-45, 53-54 are expected to happen upon execution of the method in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 12/23/2025 have been fully considered but they are not persuasive.
Concerning Mullick et al reference Applicant argues that the reference does not teach a new limitation of identifying patients with specific level of triglycerides. In response the reference makes the limitation obvious as stated in a new obviousness rejection above. Further Applicant argues that the reference does not teach treatment of FCS. In response the reference specifically points out that inhibition of ApoCIII expression unexpectedly results in increased chylomicron clearance and is therefore important in the prevention of chylomicronemia (see lines 10-13 on page 6 of the reference, emphasis added). Therefore, it would be obvious to treat any chylomicronemia using inhibitors of ApoCIII.
Concerning 103 rejection based on Crooke et al reference and others Applicant argues that the references do not teach a new limitation of identifying patients with specific level of triglycerides. In response Mullick et al reference is included in modified rejection above, which teaches the new limitation.
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.
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/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637