DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., claims 1, 4, 5, 8, 9, 12, 27-29, 33, 37-45 and 49) in the reply filed on 2/03/2026 is acknowledged.
Applicants amended of claims 1, 4-5, 8-9, 12, 27-28, 37-38, 40, and 49 is acknowledged. Applicant’s cancellation of claims 13, 15, 17, 19, 21, 23, 25, 39, and 41 is acknowledged. There are new claims (i.e., claims 50-53).
Furthermore, applicant’s election of species for Group I of “spontaneous bleeding rate” without traverse is acknowledged.
Since, the applicant elected “spontaneous bleeding rate” as the single disclosed species of bleeding rate for Group I, therefore, based on that species election, claims 9, 12, and 52, are withdrawn as being drawn to a non-elected species.
Claims 1, 4, 5, 8, 27-29, 33, 37-45, 49-51, and 53 are under consideration in this office action and will be examined on the merits.
Status of Claims
Claims 1, 4, 5, 8, 27-29, 33, 37-38, 40, 42-45, and 49-51 and 53 are pending. Applicant amended claims 1, 4-5, 8-9, 12, 27-28, 37-38, 40, and 49, added claims 50-53, and canceled claims 13, 15, 17, 19, 21, 23, 25, 39, and 41.
Claims 1, 4, 5, 8, 27-29, 33, 37-38, 40, 42-45 and 49-51 and 53 are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS/s) submitted on 9/20/2023 and 2/03/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 8 and 42 are objected to because of the following informalities:
-In claim 8, the last word “zero” is typographically spelled zer.
-In claim 42, the abbreviations/acronyms; ALT, and AST are not spelled out.
Appropriate corrections are required.
Claim Rejections - 35 USC § 102
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 following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4, 5, 8, 27, 29, 33, 40, 42-45, 49-51, and 53 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Akinc et al. (“METHODS AND COMPOSITIONS FOR TREATING A BLEEDING EVENT IN A SUBJECT HAVING HEMOPHILIA”, Pub. No.: US 2020/0163987 A1; Pub. Date: May 28, 2020) herein referred to as Akinc as evidenced by Sanofi (“A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors” January 30, 2020).
As evidenced by Sanofi, the examiner notes that AT3SC is also known as Fitusiran (Title, and other study ID numbers/identifiers). In light of evidentiary reference (Sanofi), the claimed pharmaceutical product “fitusiran” will be referred herein as “AT3SC” and “AT3SC-001”. AT3SC-001 is the original investigational code name for what is now marketed as fitusiran which is an antithrombin-directed small interfering RNA (siRNA) therapeutic.
Regarding claim 1, Akinc teaches treating hemophilia A/B subjects with or without inhibitors using AT3SC-001 (aka fitusiran), including routine prophylaxis and reduction of median annual bleeding rate (ABR).
Akinc also discusses subjects previously on prophylactic replacement factors [0010, 0017, 0186-0199, 0200-0201, 0534-0560]. Akinc teaches subcutaneous administration of AT3SC-001 [0048-0049, 0200-0201, 0534-0555]. Akinc further teaches administration of a therapeutically effective amount/dose of the RNAi agent [0010-0014, 0186-0187, 0199-0201]. Akinc teaches that breakthrough bleeds may be managed with reduced doses of replacement factor/BPA after AT3SC-001, and that patients previously on prophylactic replacement factors were treated with AT3SC-001 [0054-0056, 0559-0564, 0565]. Akinc teaches that the duration of treatment is once every two months [0017]. The termination of prophylactic replacement factor or BPA treatment in the subject within about two months, about one month, or optionally within about 28 days, or about seven days, of the first dose of fitusiran is inherently contemplated for hemophilia A or B treatment. Moreover, the ordinary skilled artisan would clearly envisage terminating the prophylactic replacement factor or BPA treatment in the subject, because the additional therapy i.e., subcutaneous administration of fitusiran would necessarily require discontinuing the prophylactic approach in order to see the most effective outcome of the fitusiran administration and particularly its clinical efficacy.
Regarding claims 4, Akinc discloses median ABR of zero for inhibitor patients in part D and reduced ABR in OLE, it also reports median ABR of 1 overall in the OLE [0047, 0551-0558]. Moreover, Akinc reports historical median ABR values such as 6, 28, and higher, which are above 4, although not as a specific selection criterion [0547-0548].
Regarding claims 5, Akinc discloses reduction of spontaneous bleeds and states the median annualized spontaneous bleed rate (AsBR) was zero in the OLE [0548, 0558-0560]. Moreover, Akinc reports historical median ABR values such as 6, 28, and higher, which are above 4 [0547-0548]. Akinc further teaches patient population, prior prophylactic treatment, subcutaneous AT3SC-001, and reduced doses of replacement factor/BPA for breakthrough bleeds after AT3SC-001 as well [0010-0014, 0534-0555, 0559-0564].
Regarding claim 8, Akinc teaches that the median annualized spontaneous bleed rate was zero in the OLE study [0548, 0558-0560]. The historical bleed rate discussion is about ABR [0548], not AsBR as historical AsBR threshold is not explicitly provided. While Akinc does not explicitly teach that the administration reduces AsBR of the subject to one or less, or zero, the AsBR reduction is inherently contemplated for hemophilia A and B treatment. Additionally, the ordinary skilled artisan would clearly envisage reduction of AsBR, because reduction in median annualized spontaneous bleed rate to zero would necessarily reduce AsBR of the subject to one or less, or zero as it is a fair indicator of the expected outcome on an annual basis.
Regarding claim 27, Akinc teaches once monthly dosing and monthly fixed-dose regimens [0016-0017, 0049, 0535-0536, 0552, 0557, 0560]; it does not explicitly teach every other month or every 8 weeks that are stated in the alternate.
Regarding claim 29, Akinc teaches hemophilia A and B patients with inhibitors [0012, 0014, 0138, 0536, 0551, 0555].
Regarding claim 33, Akinc teaches hemophilia A and B subjects without inhibitors and clinical cohorts of inhibitor patients [0011, 0013, 0138, 0536, 0554- 0558].
Regarding claims 40, Akinc discloses subcutaneous administration of fitusiran at about 50 mg about once every month or once every 4 weeks [0049, 0536, 0555-0557].
Regarding claims 42, Akinc does not explicitly note the entire claimed negative exclusion set. Akinc, however notes the alternate limitation i.e., many subjects had hepatitis C history and that ALT/AST elevations occurred [0538, 0556].
Regarding claims 43, Akinc does not explicitly specify the age cutoff of 12+, however, it does teach human subjects/adults with hemophilia A and B with or without inhibitors [0017, 0134, 0534-0555].
Regarding claims 44, Akinc teaches reduced doses of replacement factors/BPAs compared to recommended doses after AT3SC-001. This supports reduced annualized consumption, though not always with a specific annualized weight-adjusted metric [0559-0564, 0568-0569].
Regarding claims 45, Akinc teaches breakthrough bleeds were successfully managed with lower doses of replacement factor/BPA and that lower doses may suffice to achieve homeostasis [0543-0544, 0559-0569].
Regarding claims 49, Akinc teaches ABR reduction, and AsBR reduction, subcutaneous fitusiran, and improved homeostasis/clinical phenotype in hemophilia patients with or without inhibitors. QoL/PRO is not as explicitly taught; however, it is necessarily inferred due to clearly taught overall therapeutic benefit [0010-0017, 0054-0056, 0186-0199, 0534-0560].
Regarding claims 50, Akinc teaches historical ABR values such as 6 and 28 which are greater than 4 [0547-0548].
Regarding claims 51, Akinc teaches bleed history that supports the fact that spontaneous bleeding existed pre-treatment, thereby meeting the limitation of historical AsBR quantified as >2. [0548, 0558-0560].
Regarding claims 53, as explained above in claims 28 and 37; Akinc explicitly teaches an alternate dosage amount of 50 mg. [0020, 0053, 0536, 0555].
Claim Rejections - 35 USC § 103
The following is a quotation of 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 of this title, 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 negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Applicant Claims
2. Determining the scope and contents of the prior art.
3. Ascertaining the differences between the prior art and the claims at issue, and resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 5, 8, 27-29, 33, 37-38, 40, 42-45, 49-51, and 53 are rejected under 35 U.S.C. 103(a) as being unpatentable over Akinc et al. (“METHODS AND COMPOSITIONS FOR TREATING A BLEEDING EVENT IN A SUBJECT HAVING HEMOPHILIA”, Pub. No.: US 2020/0163987 A1; Pub. Date: May 28, 2020) herein referred to as Akinc as evidenced by Sanofi (“A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors” January 30, 2020) and further in view of Pasi et al. (“Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy” N Engl J Med 2017;377:819-828, Published August 31, 2017).
As discussed above, and evidenced by Sanofi, the examiner notes that AT3SC is also known as Fitusiran (Title, and other study ID numbers/identifiers). In light of evidentiary reference (Sanofi), the claimed pharmaceutical product “fitusiran” will be referred herein as “AT3SC” and “AT3SC-001”. AT3SC-001 is the original investigational code name for what is now marketed as fitusiran which is an antithrombin-directed small interfering RNA (siRNA) therapeutic.
Regarding claim 28, Akinc discloses fixed doses of 25, 50, 80, and 100 mg, and broader 25-100 mg ranges [0018, 0020, 0041-0043, 0467-0475, 0536, 0555]. Akin teaches 50 mg and 80 mg and their uses clinically [0020, 0046-0047, 0535-0536, 0555]. Although Akinc does not explicitly list full dosage range (specifically 10 and 20 mg) identical to those instantly claimed, the optimum amounts of the presently claimed active agents and excipients would have been a matter well within the insight of one of ordinary skill in the art. Such a determination would have been made in accordance with a variety of factors, such as the route of administration, pharmacological considerations, such as the activity, efficacy, pharmacokinetics and toxicology profiles of the combination regimen, as well as the age, weight, sex, diet and medical condition of the patient, and the severity of the condition. Thus, the determination of the optimum or workable amounts given the guidance of the prior art would have been generally prima facie obvious to the ordinary skilled artisan. Please see MPEP 2144.05 [R-2] (II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (“[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation"). Accordingly, the particular amounts claimed do not impart patentability to the claims, absent a showing of the criticality of the particular amounts claimed.
Regarding claim 37, Akinc teaches 50 mg fixed monthly dosing, once every two months [0016, 0017, 0536, 0555, 0557] but does not explicitly teach once every 8 weeks which is recited in the alternate. As discussed above, the optimum amounts of the presently claimed active agents and excipients would have been a matter well within the insight of one of ordinary skill in the art. Such a determination would have been made in accordance with a variety of factors, such as the route of administration, pharmacological considerations, such as the activity, efficacy, pharmacokinetics and toxicology profiles of the combination regimen, as well as the age, weight, sex, diet and medical condition of the patient, and the severity of the condition. Thus, the determination of the optimum or workable amounts given the guidance of the prior art would have been generally prima facie obvious to the ordinary skilled artisan. Please see MPEP 2144.05 [R-2] (II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (“[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation"). Accordingly, the particular amounts claimed do not impart patentability to the claims, absent a showing of the criticality of the particular amounts claimed.
Regarding claim 38, Akinc teaches measuring AT levels, AT knockdown, and modeling AT/thrombin relationships [0057-0060, 0537, 0540-0542, 0550, 0571-0574]. However, Akinc does not explicitly teach the specific steady state AT-guided dosing algorithm claimed.
Pasi teaches once-monthly subcutaneous administration of fitusiran resulting in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B (Conclusions). Pasi evaluated the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran in healthy volunteers and in participants with hemophilia A or B. In addition, Pasi conducted a post hoc exploratory analysis to evaluate the effect of monthly fitusiran on bleeding frequency. A relationship between reduced levels of antithrombin and increased thrombin generation was observed in the participants regardless of the type of hemophilia. Thrombin-generation values that were associated with the greatest lowering in antithrombin levels (>75% from baseline) were consistent with those reported for mild hemophilia, which suggests that long-term fitusiran treatment may allow for the functional conversion of severe hemophilia to a milder clinical phenotype (Discussion, paragraph 2, lines 1-6).
It would have been obvious to a person having ordinary skill in the art to incorporate Akinc’s 50 mg dosage to Pasi’s analysis of Pharmacokinetic and pharmacodynamic characteristics of Fitusiran. One would have been motivated to do so in order to evaluate safety outcomes as well as better understand the significance of different AT levels including specific dosage of fitusiran, specific dosage route, and dosing frequency or discontinuing dosing.
Conclusion
Claims 1, 4, 5, 8, 27-29, 33, 37-38, 40, 42-45 and 49-51 and 53 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHAR INAM whose telephone number is (571)272-0821. The examiner can normally be reached 7:30 am-5:00 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAHAR INAM/
Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/
Supervisory Patent Examiner, Art Unit 1622
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