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 .
Status of Application/Amendment/Claims
This Office action is in response to the communications filed on January 9, 2026.
Currently, claims 2, 6, 14, 18, 25, 28-33, 35-38, 40, 42, 44-45, and 103-108 are pending and under examination on the merits in the instant application.
The following rejections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections/objections not repeated in this Office action are hereby withdrawn.
Maintained Objections/Rejections
Priority
The priority benefit remains denied for claims 2, 6, 14, 18, 25, 28-33, 35-38, 40, 42, 44-45, and 103 for the reasons as set forth in the Office action mailed on July 15, 2025 and for the reasons set forth below.
Applicant's arguments filed on January 9, 2026 have been fully considered but they are not persuasive. Applicant argues that the prior-filed applications disclose “the data necessary to support” the claimed subject matter by pointing to the declaration filed on January 9, 2026. In response, applicant’s inability to specifically point out the actual “data” (e.g., an actual reduction to practice) in any of the prior-filed applications that indeed fully, sufficiently describe and support the instantly claimed method with all of the claimed limitations appears to support the examiner’s position that the instantly claimed therapeutic method was not completed as of the prior-filed applications’ filing dates.
Regarding the aforementioned declaration, the declaration filed under 37 C.F.R. §1.132 is not found sufficient to support applicant’s argument for the following reasons:
In paragraph 19, the declarant appears to imply that the ‘046 provisional application filed on August 5, 2019 discloses the dosing schedule/frequency claimed in the instant case by pointing out paragraph 0124. In response, it is noted that paragraph 0124 of the ‘046 application is completely silent regarding the instantly claimed administration of two “about 25 mg” doses that are “about three months” apart from each other, wherein the two doses are administered to a human subject having the claimed diseases. It is noted that paragraph 0124 pertains to the results summarized in Table 4, which discloses multiple doses only in relation to “two monthly (i.e., days 1 and 29)” and nothing else, wherein the “two monthly” dose is a mere prophetic, future plan. That is, Table 4 at best shows that only a single dose administration was actually performed. Furthermore, paragraph 0124 and Table 4 are completely silent regarding the “third dose” and “additional doses after the third dose” claimed in the instant case. It is unclear how Table 4 or paragraph 0124 can possibly describe the instantly claimed “about three months” of dosing interval for the two doses of “about 25 mg”, let alone the additional doses that are up to “about six months apart” when such disclosure is nowhere to be found. Interestingly, the declarant states in paragraph 20 that he himself “had a reasonable belief that a dose of 25 mg administered once every three months would be a therapeutically viable dose”, which is allegedly supported by paragraph 0125 disclosing “quarterly dosing at 25 mg”. As an initial matter, applicant’s attention is directed to the fact that what the declarant, one of the co-inventors, believed has no relevance to the written description issues. The “reasonable belief” held by the declarant is a far cry from showing that the ‘046 specification itself provides adequate written description support “in such full, clear, concise, and exact terms” for the instantly claimed dosing schedule/intervals, which must result in the treatment of various diseases as well as reduced levels of serum lipids in the treated patient having an APOC3-associated disease in a human patient as required by the claims. Now, regarding the “quarterly dosing at 25 mg” disclosed in paragraph 0125, it is noted that the disclosure at best supports a future plan to try four doses of 25 mg, each of which is administered quarterly (every three months), wherein such future plan is far from supporting the instantly claimed dosing schedule/intervals, wherein the second dose is administered “about three months after the first dose” and the “additional doses after the third dose” are administered up “to about six months apart.” In addition, the passage in paragraph 0125 pertains only to the speculation/future plan that a “quarterly dosing at 25 mg” can be used “to achieve substantial APOC3 gene expression inhibition”, not to treat a subject having an APOC3-associated disease such as dyslipidemia, obesity, chylomicronemia, hypertriglyceridemia, and FCS with a required 50% reduction in serum TG as well as reductions in serum VLDL-C and serum LDL-C as claimed in the instant case. The mere possibility of achieving serum APOC3 gene expression inhibition via quarterly dosing is not the same as providing the claimed, required physiological effects in a human patient suffering from an APOC3-associated disease/condition. Most importantly, the prophetic multiple dosing schedule in Table 4, which at best supports two doses administered on “days 1 and 29” at “50 mg”, is nowhere close to the instantly claimed dosing schedule/intervals, nor does the actual single administration of 25 mg to “healthy volunteers” represent the instantly claimed administration performed in a human patient suffering from a disease associated with APOC3. Again, the actual single dose administration of the claimed RNAi molecule was practiced in healthy subjects: “healthy volunteers, adult males and females, aged 18-65 years with BMI between 19.0 and 40.0 kg/m2”. See Table 4. There is no disclosure/evidence in the ‘049 application that the “heathy volunteers” qualify as the instantly claimed “human subject in need” of being treated for “an APOC3-related disease or disorder” including but not limited to “hypertriglyceridemia, obesity, dyslipidemia, non-alcoholic steatohepatitis,…familial partial lipodystrophy.”
The declarant further points out claims 2 and 9 of the ‘046 provisional application as providing support for the instantly claimed method. In response, it is noted that the mere appearance of the same words/limitations in the provisional claims is not sufficient to comply with the written description requirement because there is no adequate support, other than the mere appearance of the claimed words in the provisional claims, that conveys that the instant co-inventors had possession of the instantly claimed human patient treatment method with all of claimed limitations including the treatment of specific diseases and specific physiological changes in the serum sample of the treated patient by providing the specific dosing at the specified dosing intervals.
“The appearance of
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mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement... If a purported description of an invention does not meet the requirements of the statue, the fact that it appears as an original claim or in the specification does not save it. A claim does not become more descriptive by its repetition, or its longevity.” (emphasis added). Enzo Biochem Inc. v. Gen-Probe Inc. 323 F3d 956, 63 USPQ2d 1609 (Fed. Cir. 2002).
In paragraphs 22-24, the declarant points out “Exhibit C”, which does not support that the ‘046 application itself describes the instantly claimed subject matter with all of its limitations so as to reasonably convey that the instant co-inventors had possession of the claims as now written as of the ‘046 application filing date. The declarant states that the FDA-approved dosing regimen in “Exhibit C” is a mere confirmation of the disclosure in Example 2 of the ‘046 provisional application. The examiner fails to understand how “Exhibit C” with the revised date of “11/2025” (November, 2025) after more than six years elapsed since the ‘046 application filing date can possibly demonstrate that the ‘046 application itself demonstrates possession of the claimed subject matter with all of its claimed limitations as of August 5, 2019.
“Nor is it sufficient [to comply with the written description requirement], as
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Ariad argues, that “skilled workers actually practiced this teaching soon after the 1989 application was filed.” See Vas-Cath, 935 F.2d at 1563-64 (holding that a written description analysis occurs “as of the filing date sought”)…. Conversely, we have repeatedly stated that actual “possession” or reduction to practice outside of the specification is not enough. Rather, as stated above, it is the specification itself that must demonstrate possession.” (emphasis added). Ariad Pharmaceuticals Inc. v. Eli Lilly & Co. 593 F3d 1336, 94 USPQ2d 1161 (Fed. Cir. 2010).
Again, the ’046 provisional application does not describe that the 25 mg dosage administered three months apart between the first two doses results in the treatment of various diseases such as “dyslipidemia”, “obesity”, “chylomicronemia”, “hypertriglyceridemia”, and “FCS” in a human subject in need thereof as required by the instant claims, nor does the provisional application describe that the instantly recited dose and the dosing intervals result in the reduced serum levels of VLDL-C, LDL-C, and TG in a human subject having the APOC3-related disease. There is no adequate written description support whatsoever for the required nexus between the claimed dose and dosing schedule and the recited clinical effects in a human subject having a wide range of APOC3-related diseases, and the §1.132 declaration is insufficient to show that the ‘046 provisional application itself demonstrates possession of the instantly claimed APOC3-related disease treatment method as of August 5, 2019. There is simply no written description in the ‘046 provisional application that sufficiently supports the clinical nexus between the specific dose (about 25 mg) at specific dosing intervals (about three months apart) and the treatment of a human patient having the recited diseases, wherein the treatment results in the specified effects in serum lipids when the ‘046 provisional application at best adequately describes an actual reduction to practice a single dose administered to healthy volunteers, especially in view of the express prophetic disclosure that “two doses of 50 mg will be administered to FCS patients (Cohort 5)” on “days 1 and 29”. See Table 4 and 0121.
In view of the foregoing, the priority benefit denial is maintained.
Claim Rejections - 35 USC § 112
Claims 2, 6, 14, 18, 25, 28-33, 35-38, 40, 42, 44-45, and 103 remain rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement for the reasons as set forth in the Office action mailed on July 15, 2025 and for the reasons set forth below.
Applicant's arguments filed on January 9, 2026 have been fully considered but they are not persuasive. Applicant points out “Example 2” of the instant specification. In response, it is noted that “Example 2” pertains to “day 1 and day 29” dosing schedule practiced in five “all chylomicronemia patients”, who showed reduced levels of serum APOC3 protein and serum triglycerides. As such, Example 2 is far from supporting the instantly claimed dosing schedule/intervals for the genus of human patients having any APOC3-associated disease. Applicant did not elaborate how or why “Example 2” supports and describes the claims as currently written.
Applicant argues that the claims comply with the written description requirement by pointing to the concurrently filed §1.132 declaration. In particular, applicant states on the record that “the specification provides concrete experimental results from which the inventors, including Dr. Hamilton himself, reasonably inferred the suitability of dosing intervals of 25 mg dose administrated every three months”. In response, it is noted what the declarant/inventor “inferred” and actually practiced after the instant application’s filing date cannot provide any objective evidence that the instant specification itself describes the instantly claimed human patient treatment method as currently written with all of its limitations in such a manner that the instant specification itself demonstrates possession. Applicant’s attention is directed to the fact that a written description inquiry/analysis occurs as of the filing date sought, not after the filing date. In addition, applicant’s inability to specifically point out the alleged “concrete experiential results” in the instant specification that describe the claimed therapeutic method with all of the claimed limitations appears to support the examiner’s position that the instant specification fails to describe the claimed method in the manner to reasonably convey that the instant co-inventors completed and had possession of the methods as currently written as of the instant application’s filing date.
Now, since applicant’s arguments are primarily based on and refer to the declaration, the examiner will address the declaration.
The declaration filed under 37 C.F.R. §1.132 is insufficient to overcome the instant rejection for the following reasons:
The declarant expressly admits on the record that his “best guess” was that “an approximately 200 mg dose would most likely be necessary to achieve the APOC3 inhibition needed to obtain a therapeutic benefit in patients.” See paragraph 17. The declarant then states in paragraph 20 that he “had a reasonable belief that a dose of 25 mg administered once every three months would be a therapeutically viable dose” after the clinical trial protocol involving healthy volunteers as disclosed in the provisional application. In response, it is noted that the “guess” and “belief” of the declarant do not qualify as objective, factual evidence showing that the instant specification itself demonstrates possession of the instantly claimed treatment method as of the instant application’s filing date. The law requires that the specification, not co-inventor’s guesswork or belief, must describe the claimed invention. In addition, the declarant did not provide any supporting objective evidence as to why the 25 mg single dose tested in healthy volunteers can possibly support the multi-dosing regimen applied to a human patient having an APOC3-related disease.
The declarant states that paragraph 0143 discloses “quarterly dosing at 25 mg”. In response, it is noted that the disclosure at best supports a future plan to try four doses of 25 mg, each of which is administered quarterly (every three months), wherein such future plan is far from supporting the instantly claimed dosing schedule/intervals, wherein the second dose is administered “about three months after the first dose” and the “additional doses after the third dose” are administered up “to about six months apart.” In addition, the passage in paragraph 0143 pertains only to the speculation/future plan that a “quarterly dosing at 25 mg” can be used “to achieve substantial APOC3 gene expression inhibition” in serum, not to treat a subject having an APOC3-associated disease such as dyslipidemia, obesity, chylomicronemia, hypertriglyceridemia, and FCS with a required 50% reduction in serum TG as well as reductions in serum VLDL-C and serum LDL-C as claimed in the instant case. The mere possibility of achieving serum APOC3 gene expression inhibition is not the same as providing the claimed, required physiological effects in a human patient suffering from an APOC3-associated disease/condition.
The declarant states the clinical data in the specification “reasonably support a viable dosing regimen for patients” at the instantly claimed dosing schedule, which “could lead to a physiological benefit in patients.” In response, it is noted that the declarant’s speculation is not supported by the instant specification, which at best describes the following in relation to a therapeutic method performed in a human patient having an APOC3-related disease: “day 1 and day 29” dosing schedule at “50 mg” administered to five “chylomicronemia patients” (“Cohort 5”), who showed reduced levels of serum APOC3 protein and serum triglycerides. As such, the examiner is bewildered by how the declarant is able to assert on the record in the §1.132 declaration that the instantly claimed dose/dosing intervals are reasonably supported by the instant specification’s disclosure, which does not provide any adequate therapeutic method description with all of the limitations recited in the instant claims. The two doses of “50 mg” administered on day 1 and day 29 to chylomicronemia patients do not whatsoever resemble the instantly claimed multi-dosing regimen of “about 25 mg” administered about three months apart to a human patient having any APOC3 disease. That is, the data disclosed in the instant specification are not representative or indicative of the instantly claimed therapy method and as such, the examiner strongly disagrees with the declarant’s assertion that the instant specification’s clinical data “reasonably support” the instantly claimed human patient treatment method as now written.
The declarant states that the instantly claimed “APOC3 RNAi Drug Substance” has been FDA-approved for reducing triglycerides in FCS adult patients by pointing out “Exhibit C”, which shows 25 mg dose that is “injected subcutaneously once every 3 months.” In response, it is noted that “actual “possession” or reduction to practice outside of the specification is not enough. Rather, as stated above, it is the specification itself that must demonstrate possession.” (emphasis added). Ariad Pharmaceuticals Inc. v. Eli Lilly & Co. 593 F3d 1336, 94 USPQ2d 1161 (Fed. Cir. 2010). In addition, it is noted that the single disease, FCS, in “Exhibit C” is not a representative number of APOC3-associated diseases, and similarly, the reduction of a single lipid species, triglyceride, is not representative of VLDL-C and LDL-C. Again, the post-filing data, namely “Exhibit C”, cannot support that the instant specification itself describes an FCS patient treatment method by subcutaneous injection once every 3 months at the fixed dose of 25 mg as “actual “possession” or reduction to practice outside of the specification is not enough.”
It is interesting to note that the declarant expressly acknowledges on the record that “at the time of designing the Phase I trial for plozasiran, the dosing interval necessary to obtain a therapeutic benefit was uncertain”. See paragraph 17. Now, it is noted that the actual data in Table 4 including the twice monthly (days 1 and 29) at 50 mg administered to FCS patients is titled “Phase I Clinical Trial”. See paragraph 0139. Hence, it is prima facie apparent that the instant specification itself unequivocally fails to describe the necessary nexus between the instantly claimed “about 25 mg” fixed dose administered at about 3 months apart to human patients having FCS or other APOC3-related diseases as evidenced by the uncertainty of the declarant, also a named co-inventor, regarding “the dosing interval necessary to obtain a therapeutic benefit”.
Accordingly, this rejection is maintained.
Claim Rejections - 35 USC § 103
Claims 2, 6, 14, 18, 25, 28-33, 35-38, 40, 44-45, and 103 remain rejected under 35 U.S.C. 103 as being unpatentable over Li et al. in view of Chan et al. for the reasons as set forth in the Office action mailed on July 15, 2025 and for the reasons set forth below.
Applicant's arguments filed on January 9, 2026 have been fully considered but they are not persuasive. Applicant argues that the claims are not obvious because Li does not teach the claimed dosing regimen. In response, applicant’s attention is directed to the fact that the instant rejection is not established solely on Li and therefore, applicant cannot show nonobviousness by attacking Li alone. Note that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that Chan in combination with Li would not lead to the instant claims because Chan’s disclosure pertains to an entirely different RNAi molecule targeting an entirely different target than what is being claimed and taught by Li. In so arguing, applicant points out paragraph 11 of the §1.132 declaration. In response, it is noted that the differences in the RNAi molecule and the disease in Chan compared to Li are not sufficient to render the instantly claimed subcutaneous dosing schedule/intervals nonobvious because Li’s subcutaneous injection of a APOC3-targeting, GalNAc-conjugated RNAi molecule is taught to be delivered to the liver in order to provide a therapeutic effect just like Chan’s subcutaneous injection of a TTR-targeting, GalNAc-conjugated RNAi molecule at 25 mg that is also delivered to the liver tissue for treating a TTR-associated disease. That is, the liver is the primary organ that is targeted by the RNAi molecules of both Li and Chan via the GalNAc conjugate, and furthermore, the route of delivery/administration of the RNAi molecules of both Li and Chan is identical: subcutaneous injection. Moreover, Li’s injection of the effect of APOC3-targeting RNAi molecule into NHP was shown to last up to 50 days (about 2 months) as the RNAi molecule reduced APOC3 mRNA expression by about 80% in NHP on day 50 after the single injection. As such, a person of ordinary skill in the art who is not an automaton but a person with ordinary creativity would have reasonably deemed Chan’s “once about every three months” dosing schedule/interval would be applicable/suitable to provide the intended treatment for an APOC3-targeting RNAi molecule that is to be delivered to the liver via the GalNAc conjugate. Note that a “person of ordinary skill is also a person of ordinary creativity, not an automaton.” KSR. International Co. v. Teleflex Inc., 550 US 398, 421, 82 USPQ2d 1385, at 1397 (U.S. Supreme Court, 2007).
Now, regarding paragraph 11 of the §1.132 declaration pointed out by applicant, it is noted “Exhibit B” mentioned in paragraph 11 pertains to a subcutaneous injection of two first doses of 284 mg of a PCSK9-targeting, liver-directed, GalNAc-conjugated RNAi molecule that is 3 months apart for lowering cholesterol in a human subject in need thereof, wherein the finally FDA-approved 284 mg unit dosage is not the only dose tested. That is, the RNAi molecule was tested “over a range from 25 mg to 800 mg” (emphasis added). See section 12.3. That is, the mere fact that the optimal single unit dose for the particular RNAi molecule targeting PCSK9 was finally determined to be 284 mg through art-accepted routine dosing optimization does not whatsoever teach away from trying the 25 mg dose once every three months as taught by Chan as it is evident that dosage optimization was routine in view of the teachings of Li, Chan, and “Exhibit B”. Furthermore, the dosing regimen wherein the first two doses are 3 months apart from each other is also practiced for the PCSK9-targeting RNAi molecule just like Chan’s TTR-targeting RNAi molecule. That is, although the optimal dosage finally determined to be effective for providing the intended effects by the PCSK9-targeting RNAi is not the same as what is being claimed for the APOC3-targeting RNAi in the instant case, the dosing schedule of once every three months was art-accepted dosing schedule. As such, the instantly claimed dosing schedule/intervals taught by Chan is indeed corroborated by and consistent with “Exhibit B”.
Applicant points out paragraph 17 of the declaration and argues that the claimed RNAi was tested in animals and a dose of about 200 mg or higher was deemed necessary for therapeutic use thus, the claims are not obvious. In response, it is noted that the declarant’s statement does not relate to the obviousness rationale set forth in the instant rejection. That is, the declarant’s opinion on Li’s data relating to NHP and his “best guess” being about 200 mg dose for therapeutic efficacy in human patients does not address why one of ordinary skill in the relevant art would not have considered Chan’s fixed dose and dosing interval relevant to human subject “in order to save time, expense, and resources by bypassing testing numerous different dosing schedules using different doses” as set forth in the last Office action.
Accordingly, this rejection is maintained.
Claim 42 remains rejected under 35 U.S.C. 103 as being unpatentable over Li et al. in view of Chan et al. and Manku et al. for the reasons as set forth in the Office action mailed on July 15, 2025 and for the reasons set forth below.
Applicant's arguments filed on January 9, 2026 have been fully considered but they are not persuasive. Applicant argues that the claim is not obvious because the cited art does not suggest the instantly claimed dose and dosing schedule. Contrary to applicant’s argument, the cited references in combination suggest the instantly claimed “about 25 mg” multi-dose administered about three months apart as explained in the last Office action and further explained hereinabove. Accordingly, this rejection is maintained.
Double Patenting
Claims 2, 6, 14, 18, 25, 28-33, 35-38, 40, 42, 44-45, and 103 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26-37 of U.S. Patent No. 10,597,657 B2 in view of Chan et al. and Manku et al. for the reasons as set forth in the Office action mailed on July 15, 2025 and for the reasons set forth below.
Applicant's arguments filed on January 9, 2026 have been fully considered but they are not persuasive. Applicant argues that the claimed dosing regimen was not suggested by the cited secondary references. Contrary to applicant’s argument, the instantly claimed dosing regimen is suggested by Chan, and the §1.132 declaration of record is not found effective to show the asserted nonobviousness of the instant claims in view of Chan. Further, “a dose of about 0.05 mg/kg to about 5.0 mg/kg of body weight of the human subject” as broadly claimed in the ‘657 patent does clearly read on the fixed dose of about 25 mg. For instance, a dose of about 0.4 mg/kg claimed in the ‘657 patent would be 26 mg (thus about 25 mg) for a human subject whose body weight is 65 kg.
Accordingly, this rejection is maintained.
Claims 2, 6, 14, 18, 25, 28-33, 35-38, 40, 42, 44-45, and 103 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18-30 of U.S. Patent No. 11,214,801 B2 in view of Chan et al. and Manku et al. for the reasons as set forth in the Office action mailed on July 15, 2025 and for the reasons set forth below.
Applicant's arguments filed on January 9, 2026 have been fully considered but they are not persuasive. Applicant argues that the claimed dosing regimen was not suggested by the cited secondary references. Contrary to applicant’s argument, the instantly claimed dosing regimen is suggested by Chan, and the §1.132 declaration of record is not found effective to show the asserted nonobviousness of the instant claims in view of Chan. Further, “a dose of about 0.05 mg/kg to about 5.0 mg/kg of body weight of the human subject” as broadly claimed in the ‘801 patent does clearly read on the fixed dose of about 25 mg. For instance, a dose of about 0.4 mg/kg claimed in the ‘801 patent would be 26 mg (thus about 25 mg) for a human subject whose body weight is 65 kg.
Accordingly, this rejection is maintained.
Claims 2, 6, 14, 18, 25, 28-33, 35-38, 40, 42, 44-45, and 103 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-22 of U.S. Patent No. 12,365,899 B2 in view of Chan et al. and Manku et al. for the reasons as set forth in the Office action mailed on July 15, 2025 and for the reasons set forth below.
Applicant's arguments filed on January 9, 2026 have been fully considered but they are not persuasive. Applicant argues that the claimed dosing regimen was not suggested by the cited secondary references. Contrary to applicant’s argument, the instantly claimed dosing regimen is suggested by Chan, and the §1.132 declaration of record is not found effective to show the asserted nonobviousness of the instant claims in view of Chan. Accordingly, this rejection is maintained.
New Objections/Rejections Necessitated by Amendment
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of all of the four prior-filed applications fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. It is noted that claims 104-108 directly depend from claim 2. The reasons for finding a lack of a written description for claim 2 in the ‘046 application as well as the instant application are explained in detail hereinabove in this Office action hence will not be repeated herein. Since claims 104-108 each depend from claim 2, it is concluded that the prior-filed applications fail to support/describe claims 104-108 for the same reasons as provided hereinabove. Accordingly, claims 104-108 are not entitled to any of the prior-filed application filing dates. As such, the effective filing date for claims 104-108 will be the instant application’s filing date.
Claim Rejections - 35 USC § 112
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 103-108 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 103-108 directly depend from claim 2, which is found to lack adequate written description support by the instant specification as explained in detail hereinabove, which is fully incorporated by reference herein. Hence, by virtue of claim dependency, it is concluded that the instant specification fails to describe claims 103-108 in sufficient detail in the manner to reasonably convey that the instant co-inventors completed and had possession of the entire genus as of the instant application’s filing date. To briefly reiterate, the instant specification’s disclosure pertaining to “day 1 and day 29” dosing schedule at “50 mg” administered to five “chylomicronemia patients” (“Cohort 5”), who showed reduced levels of serum APOC3 protein and serum triglycerides, is not representative of the instantly claimed two-dose regimen of “about 25 mg” administered “about three months” apart from each other in a method of treating a human patient having any APOC3 disease. There is nothing, other than mere appearance of words, in the instant specification that adequately substantiates and describes the instantly claimed method in the manner for one of ordinary skill in the art to conclude that the instant co-inventors had possession of claims 103-108 as of the instant application’s filing date.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 103-108 are rejected under 35 U.S.C. 103 as being unpatentable over Claims 2, 6, 14, 18, 20, 23, 25-26, 28-33, 35-38, 40, 44-45, and 103 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (US 2019/0078088 A1, of record) in view of Chan et al. (US 2019/0350962 A1, of record).
Li discloses that a single subcutaneous injection of APOC3-targeting “AD05876” comprising “AM06743-AS” and “AM07748-SS” at 3.0 mg/kg significantly reduces APOC3 mRNA expression by about 80% in non-human primates when measured on day 50. See paragraphs 0384-0386; Tables 39-40
Li discloses a single subcutaneous injection of the same agent “AD05876” on day 1 at 4.0 mg/kg resulted in a significant reduction in APOC3 protein by about 3-fold on day 29 and triglyceride levels by about 2-fold on day 29 compared to saline controls in non-human primates fed high fructose corn syrup (HFCS) diet known to cause the non-human primates “to develop increased plasma triglycerides”, wherein the reduced triglyceride levels are maintained when measured on day 36 following a second injection on day 29. See paragraph 0387; Tables 41-42.
It is noted that the antisense strand “AM06743-AS” (see Table 4) and the sense strand “AM07748-SS” (see Table 5) of “AD05876” are 100% identical to those recited in the instant claims as shown below.
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Li taches that the APOC3-targeting RNAi agent “is prepared as a sodium salt” and can be “packaged in a kit, container, pack, dispenser, pre-filled syringes, or vials.” (emphasis added). See paragraphs 0046 and 0162.
Li teaches that the APOC3-targeting RNAi agent is useful for treating an APOC3-related disease in a human patient, wherein the disease includes hypertriglyceridemia with recurrent pancreatitis, familial chylomicronemia syndrome, and hyperlipidemia. See paragraphs 0004, 0008-0009, and 0038. Hence, Li claims a method of treating the disease comprising administering “two or more doses” of the RNAi agent that reduces triglyceride levels. See claims 51-57 and 59 reproduced below.
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Li does not teach that the “two or more doses” of the RNAi agent are administered about every three months.
Chan teaches a method of treating a human patient comprising subcutaneous administration of “a fixed dose of about 25 mg to about 50 mg” of a chemically modified, GalNAc-conjugated, liver gene-targeting siRNA molecule that “is administered to the human subject every three months” such as “once about every three months”, “wherein the subcutaneous administration of self administration”, which is “via a pre-filled syringe”, wherein the siRNA molecule is fully chemically modified in both strands. See claims 1-33.
It would have been obvious to one of ordinary skill in the art before the effective filing date to try Chan’s siRNA dosing regimen that provides repeated subcutaneous injection once about every three months at a fixed dose of 25 mg packaged in “container, pack, dispenser, pre-filled syringes, or vials” when practicing Li’s claimed method. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to save time, expense, and resources by bypassing testing numerous different dosing schedules using different doses for “two or more doses” at “a dose of about 0.05 mg/kg to about 5.0 mg/kg” claimed by Li, because there was extremely useful, pertinent information provided by Li’s disclosure pertaining to the long-term in vivo efficacy of Li’s RNAi agent “AD05876” that is identical to the RNAi agent administered in the rejected claims, wherein Li’s disclosure amply suggests that a long-lasting reduction in the expression levels of the target, APOC3, as well as the triglyceride levels can be achieved by a single subcutaneous injection in a human subject in view of Li’s NHP studies such that a single subcutaneous injection of the therapeutically effective “AD05876” provided about 80% reduction in APOC3 mRNA expression in the liver tissue samples of NHP compared to pre-dose levels when measured on day 50 (see Tables 39-40) and also provided about 3-fold reduction in APOC3 protein expression levels and about 2-fold reduction in the elevated triglycerides in the NHP fed HFCS diet compared to the saline controls when measured on day 29 (see Tables 41- 42). As such, a person of ordinary skill in the relevant art would have been able to reasonably predict, based on the evidence disclosed in Li pertaining to the durable effect of “AD05876”, that the desired decreased levels of APOC3 and accompanied effects of the decreased level of APOC3 (e.g., decreased triglycerides) could reasonably last beyond 50 days (about 2 months) in a human subject thus would have tried the art-recognized siRNA therapy dosing frequency of “once about every three months” of Chan for Li’s claimed “two or more doses” in the treatment method without the need to invest in time, expense, and resources. In addition, one of ordinary skill in the art would have deemed using a “container, pack, dispenser, pre-filled syringes, or vials” containing a “fixed dose” of Li’s therapeutic RNAi agent “AD05876” would be more convenient for users including patients for “self administration” or medical professionals treating the patients instead of adjusting doses depending on the body weight of the patient, especially in view of the fact that it was an art-recognized methodology to utilize a “container, pack, dispenser, pre-filled syringes, or vials” as expressly disclosed by Li, wherein it was known in the art to utilized a pre-filled syringe containing “a fixed dose of about 25 mg” of a chemically modified, GalNAc-conjugated liver gene-targeting siRNA for self-administered subcutaneous injection as disclosed by Chan.
Accordingly, claims 104-108 taken as a whole would have been prima facie obvious before the effective filing date.
Double Patenting
The text of the judicially created doctrine not included in this action can be found in a prior Office action.
Claims 104-108 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26-37 of U.S. Patent No. 10,597,657 B2 in view of Chan et al. (US 2019/0350962 A1, of record) and Li et al. (US 2019/0078088 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by and/or would have been obvious over the ‘657 patent claims drawn to a method of treating an APOC3-related disease in a human subject in need thereof by administering an APOC3-targeting RNAi agent that is identical to the agent claimed in the instant case, wherein the RNAi agent at about 0.05 mg/kg to 5.0 mg/kg “is administered in two or more doses” via “subcutaneous injection.” It would have been obvious to provide “two or more doses” that are three months apart from each other at a fixed dose syringe containing about 25 mg because such siRNA therapy dosing regimen using a liver gene-targeting chemically modified, GalNAc-conjugated siRNA was already known in the relevant art as evidenced by Chan thus one skilled in the relevant art would have tried the already known dosing regimen with a reasonable expectation of success. Further, it was also known in the art to package an APOC3-targeting RNAi agent in “container, pack, dispenser, pre-filled syringes, or vials.” See paragraph 0046 of Li. Hence, claims 104-108 are nothing but an obvious variation of the ‘657 patent claims in view of Chan and Li.
Claims 104-108 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18-30 of U.S. Patent No. 11,214,801 B2 in view of Chan et al. (US 2019/0350962 A1, of record) and Li et al. (US 2019/0078088 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by and/or would have been obvious over the ‘801 patent claims drawn to a method of treating an APOC3-related disease in a human subject in need thereof by administering an APOC3-targeting RNAi agent that is identical to the agent claimed in the instant case, wherein the RNAi agent at about 0.05 mg/kg to 5.0 mg/kg “is administered in two or more doses” via “subcutaneous injection.” It would have been obvious to provide “two or more doses” that are three months apart from each other at a fixed dose syringe containing about 25 mg because such siRNA therapy dosing regimen using a liver gene-targeting chemically modified, GalNAc-conjugated siRNA was already known in the relevant art as evidenced by Chan thus one skilled in the relevant art would have tried the already known dosing regimen with a reasonable expectation of success. Further, it was also known in the art to package an APOC3-targeting RNAi agent in “container, pack, dispenser, pre-filled syringes, or vials.” See paragraph 0046 of Li. Hence, claims 104-108 are nothing but an obvious variation of the ‘801 patent claims in view of Chan and Li.
Claims 104-108 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15-22 in U.S. Patent No. 12,365,899 in view of Li et al. (US 2019/0078088 A1, of record) and Chan et al. (US 2019/0350962 A1, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been obvious over the patent claims drawn to a method of treating an APOC3-related disease by administering an APOC3-targeting RNAi agent that is identical to the agent claimed in the instant case. One of ordinary skill in the art would have been motivated to repeat the ‘899 patent claims at 3-month interval because “two or more doses” of the APOC3-targeting RNAi agent were known to be useful for treating an APOC3-related disease as evidenced by Li (see claim 55), and furthermore, one of ordinary skill in the art would have administered the “two or more doses” that are three months apart from each other at a fixed dose syringe containing about 25 mg because such siRNA therapy dosing regimen using a liver gene-targeting chemically modified, GalNAc-conjugated siRNA was already known in the relevant art as evidenced by Chan thus one skilled in the relevant art would have tried the already known dosing regimen with a reasonable expectation of success. Further, it was also known in the art to package an APOC3-targeting RNAi agent in “container, pack, dispenser, pre-filled syringes, or vials.” See paragraph 0046 of Li. Hence, claims 104-108 are nothing but an obvious variation of the ‘899 patent claims in view of Chan and Li.
Conclusion
No claim is allowed.
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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/DANA H SHIN/Primary Examiner, Art Unit 1635
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