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 .
Response to Amendments
Applicant’s amendments to the claims of September 2, 2025, in response to the Office Action of May 2, 2025, are acknowledged.
Response to Arguments
The rejections over Windyga are withdrawn in view of the amendments to the claims. In particular, Applicant has amended the claims to require at least one second dose to be administered every 8 to 12 hours for about 3 days. An indefiniteness rejection is applied below in view of this new language. In particular it is not clear how a single dose can be administered for about 3 days unless it is a 3 day infusion, which does not appear to be intended nor supported by the instant Specification.
The examiner interprets this to include one second dose for “up to” 3 days, which is inclusive of a single second dose. The phrase “up to” should be added to claim 1 for clarity.
The examiner notes that while Scheiflinger does not teach the identical dosing schedule claimed, Scheiflinger does teach one or more repeated doses of rVWF alone or with FVIII together. Further, subsequent repeat administrations will depend on the coagulation disease/condition to be treated. See par. 206. The VWF:Rco activity of the VWF is taught to be monitored with an ELISA reader. See par. 160. Single or multiple administrations are carried out depending on the level of severity of disease to be treated and whether prevention or treatment is desired. See par. 205. Scheiflinger explains an advantage to include flexibility to redoes as needed. Paragraph 203 explains:
[0203] One of the advantages of administering rVWF to subjects to treat coagulation disease is that the higher specific activity of rVWF as compared to pdVWF allows flexibility in the amount of rVWF administered and the number of times the subject is re-dosed with rVWF (with or without co-administered FVIII). In addition, rVWF compositions provide the further flexibility of re-dosing with rVWF alone after an initial co-administration of rVWF and without need for additional dosing with FVIII. As will be appreciated and as is discussed in further detail herein, the co-administered may be recombinant or plasma derived.
In some embodiments, the dosing is once daily. See par. 215.
Scheiflinger teaches flexibility in dosing and multiple administration, including repeat administrations depending on the severity of the disease. Further, rVWF is taught to be administered in a concentration of 0.5 IU/kg, including ranges of 30-130 IU/kg.
Further, while Federici provides teachings regarding prophylaxis, Frederici also provides teachings with respect to treatment. See Section titled “General principle for the treatment of VWD.” pS27. Treatment of patients with VWF was historically with an agent (i.e., DDAVP) that increases VWF and FVIII plasma concentrations. Those infusions would be repeated every 12 to 24 hours depending on the type and severity of the bleeding episode. Further, Frederici notes that females with menorrhagia were administered 50 U VWF:Rco/kg on days 1, 2, and 3 of menses in level 3.
Federici does provide teachings that are relevant to “on-demand” treatment for 3 consecutive days. Similarly, Scheiflinger teaches one or more repeated doses provides a road-map to determine when and how additional administration would be necessary or required. Scheiflinger teaches administration of rVWF that includes once daily. See par. 66. Moreover, the ability to determine whether sufficient levels of rVWF has been provided is known in the art in the form of, e.g., clotting assays, chromogenic assays, and immunoassays. See par. 158. Scheiflinger also teaches administration of 0.5 IU/kg, including ranges of 30-130 IU/kg while narrower ranges of 50-90, 55-80, and 60-70 IU/kg fall entirely within the claimed initial dose. See par. 207. Federici also teaches that daily monitoring of FVIII levels can be used to adjust a dosage to keep it within a desired level, such as between 50 and 150 U/dL. See pS28, col. 2.
Applicant argues that Federici teaches away from the claimed invention.
Th examiner notes that while Federici provides teachings on prophylaxis and treatment, a reference is prior art for all that it teaches. In this case, a goal of treatment and a target level of FVIII, and therapeutic approaches, are taught by Federici.
Applicant argues that the teachings away include a note that optimal therapy “may be secondary long-term prophylaxis.”
The examiner notes that a suggestion for prevention does not mean that treatment will not also be necessary when prevention does not work. Moreover, a teaching away is not merely a suggestion to try an alternative because it may be more successful. A teaching away requires a level of disparagement, which is not present in any of the cited prior art.
Applicant argues that the therapy taught by Federici shows that subjects can received treatment on days 1, 2, and 3.
Applicant argues that a specific species of a genus may be patentable relative to a genus.
The examiner notes that the claimed subject population is taught to be treated with the claimed agent. Further, the claimed initial dose is taught with specificity and a most preferred range falls entirely within the claimed range. Subsequent repeat administrations will depend on the coagulation disease/condition to be treated. Additionally, single or multiple administrations are carried out depending on the level of severity of disease to be treated and whether prevention or treatment is desired. Daily monitoring can be undertaken using various known tools in the art, including clotting assays, chromogenic assays, immunoassays, and others, to adjust a dosage to achieve the desired levels and outcome. Such, optimization would require nothing more than routine experimentation based on the known mode of action, desired levels in a subject, and methods for measuring and adjusting a dose.
Moreover, included in independent claim 1 is a single administration of a second dose. This can include administration of an initial dose of 30 IU/kg followed by a second dose of 30 IU/kg (see claim 5) 12 hours later. This particular example falls within the scope of at least instant claims 1 and 5. This includes a total dose of 60 IU/kg over 36 hours, e.g. The prior art including Scheiflinger teaches administering single doses up to 200 IU/kg with a most preferred dose to include 60-70 IU/kg.
As such, while the timing of administrations claimed includes more frequent administrations over 3 days, the claimed embodiments also include administering the same and/or a substantially lower amount more frequently. Even for those claims directed to a “plurality” of doses every 8 to 12 hours, it is not clear that the amount administered to a subject would exceed 200 IU/kg. If, e.g., 30 IU/kg is administered twice daily for 3 days the administration would equate to a dosage of 180 IU/kg in total. At most, the instant claims are directed to monitoring a subject to adjust a dose while administering a high dose for a single administration that is spread out over a period of 3 days.
Unexpected results in the form of a critical range are not alleged and shown. As such, the examiner is determining if a prima facie showing is established in view of the cited prior art. Here, the claimed API is known to treat a claimed subject through a known mechanism of action, whereby the claimed dose is taught to be administered and PK parameters are measurable and known to be used in adjusting a dosage to meet a patient’s needs. Applicant’s claims herein appear to take a known effective dose and spread it out over a period of days. Without a showing of a criticality of claimed dosage or timing of administration, such distinction does not appear to constitute a patentable distinction over the cited prior art.
Status of the Claims
Claims 1-13, 15, 17-20, 23, 25-27, 30, 32-40, 46 and 60 are pending and examined.
Claim Rejections - 35 USC § 112
Claims 1-12, 15, 17-20, 23, 25-27, 30, and 32-39 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims now require only a single second dose. As such, a single second dose cannot be administered for about 3 days unless it is an infusion., which does not appear to be what is described in the Specification or intended. Claim 1 is interpreted to include a second dose that is administered 8 to 12 hours after a first dose. This, e.g., would mean that the phrase “for about 3 days” does not apply. Clarification is requested. Adding the phrase “up to” about 3 days would appear to be consistent with the intention of the claim.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-13, 15, 17-20, 23, 25-27, 30, 32-40, 46, and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Halimeh, “Menorrhagia and bleeding disorder in adolescent females,” Hamostaseologie. 2012;32(1):45-50 (ABSTRACT), in view of Scheiflinger et al., (US2012/0316116), and in view of Federici, “Prophylaxis of bleeding episodes in patients with von Willebrand’s disease,” Blood Transfus 2008: 6 (Suppl 2): s26-s32.
Halimeh teaches von Willebrand disease (VWD) to be the most common inherited bleeding disorder and menorrhagia is the most common symptom of women with bleeding disorder symptoms. The prevalence ranges from up to 100% of subjects with VWD. Treatment options include purified blood products that contain factor VIII and VWF concentration from plasma.
Halimeh does not teach dosage regimen with specificity.
Scheiflinger teaches VWD to be a coagulation disease that that includes treatment with replacement therapy comprising normal coagulation factors. See par. 1. This replacement therapy includes administration of WVR with recombinant VWF (rVWF) alone or in combination with recombinant Factor VIII (rFVIII). See par. 5. The treatment method of anticoagulation disease with rVWF and rFVIII can result in an increased half-life of rFVIII. See par. 5. The combination can allow for lower doses and/or frequency of treatment for coagulation diseases. See par. 133. The form of VWF used can be substantially purified. See par. 152. In some embodiments, rVWF is taught to be administered in a concentration of 0.5 IU/kg, including ranges of 30-130 IU/kg. See par. 207. Overall, the safety and PK of rVWF suggest it can be used to treat and prevent bleeding episodes. See par. 316. There are several types of VWD including Types 1, 2, 2A, 2B, 2M, 2N, and 3. See Table 14. Administration can be every other day or even twice a week. See par.’s 16-17. In some examples, rVWF can be administered alone or in combination followed by one or more repeated doses of rVWF alone or with FVIII together. Subsequent repeat administrations will depend on the coagulation disease/condition to be treated. See par. 206. The VWF:Rco activity of the VWF is taught to be monitored with an ELISA reader. See par. 160. Single or multiple administrations are carried out depending on the level of severity of disease to be treated and whether prevention or treatment is desired. See par. 205. Paragraph 222 makes clear that the treatment of coagulation disease by administering rVWF or rVWF and rFVIII in need thereof can be to treat “any coagulation disease” not limited to VWF. See par. 222. In specific embodiments a level of rVWF:Rco activity includes 40 to 100 IU/kg or 75 to 125 IU/kg. See par. 237 and 268. The ratios of rFVIII to rVWF:Rco can range from 2:1 to 1:4. Further, the ratio can range from 1:1:5. See par. 176.
Scheiflinger also does not teach each dosage regimen with specificity.
Federici teaches prophylaxis preventing bleeding a number of patients with VWD as mucosal and GI bleeding can recur in some patients. See Abstract. This includes menorrhagia, as noted below. Six types of VWD are 1, 2A, 2B, 2M, 2N, and 3. Type 1 is milder than type 3 which includes those with almost no VWF in plasma and platelets. Those with milder type 1 usually have 10-30 U/dL VWF. See p27. The goal of treatment is to correct abnormal platelet adhesion and abnormal intrinsic coagulation due to low FVIII. See p27, col. 2. Therapeutic approaches include exogenous and endogenous VWF/FVIII. Frederic also explains that repeated injections of VWF/FIII concentrates can be used to control and prevent bleeding but they should be monitored for risk of DVT. Daily monitoring can be used to keep FVIII levels between 50 and 150 150U/dL and levels >30 U/dL are associated with low rate of spontaneous mucosal bleeding. These lower thresholds are identical that those set forth on page 12 of the instant Specification indicating a recommended target trough level is at least 30 IU/dL and at least 50 IU/dL in some instances. See Spec. at page 12, par. 73. Patients with recurrent GI bleeding may need treatment every day or every other day. See p28, col. 2. In other bleeders treatment can be regular and prophylactic as on demand to manage bleeding episodes. Participants were treated for GI bleeds and menorrhagia. See p31, 1st paragraph. Treatment was needed once to three times a week. Females with menorrhagia were treated on day one for two cycles and days one and two for two cycles, and days one, two, and three for two cycles. This would appear to include treatment for less than 7 days. While longer treatments are possible, for a periodic and relatively predictable episode expected to last about and/or less than one week, it would not appear necessary to treat for more than 7 days.
The examiner notes that the wherein clause in claim 60 merely indicates that treatment is efficacious as compared to no treatment. This is expected from coagulant therapy and this clause merely recites results of active steps positively recited. See M.P.E.P. § 2111.04.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to combine the teachings of Halimeh, Scheiflinger, and Federici to arrive at the claimed methods. One would be motivated to do so because the combination of prior art as a whole teaches treating a claimed subject with any type of VWD with monotherapy or combination therapy with rVWF and/or rFVIII. Further, treating and preventing a coagulation disease with the same is rendered obvious. Moreover, Willebrand disease (VWD) is the most common inherited bleeding disorder and menorrhagia is the most common symptom of women with VWD. The prevalence ranges from up to 100% of subjects with VWD. Treatment options include purified blood products that contain factor VIII and VWF concentration from plasma. rVWF and rFVIII are taught to treat such coagulation disorders at dosage ranges that overlap those claimed. Further, treatment is optimizable depending the type of VWD and the severity of an episode to be treated and/or prevented. The PK and relationship of rVWF and FVIII is established and optimizable through nothing more than routine experimentation. Optimization is particularly achievable with the known PK relationships described by the prior art, the ability to administer frequent or infrequent doses dependent upon the subject and severity of VWD as well as the known and quantitatively measurable goals of treatment, including correcting abnormal platelet adhesion and abnormal intrinsic coagulation due to low FVIII. Scheiflinger and Federici each teach treating menorrhagia is subjects with severe VWD by administering rVWF and rFVIII. Treatment can include treatment on days 1-3 of a cycle and can be for periods of less than a week as well as longer. The measurable and optimizable results provide a reasonable and predictable expectation of success in view of the cited prior art in arriving at the claimed methods.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and a range can be disclosed in multiple prior art references instead of in a single prior art reference depending on the specific facts of the case. Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1322, 73 USPQ2d 1225, 1228 (Fed. Cir. 2004). The examiner also notes that multiple administrations daily would be immediately envisaged to be spread out evenly for consistency and stability. For example, twice daily administration would be considered for every 12 hours and three times daily administration would be thought to include every 8 hours, e.g.
Conclusion
THIS ACTION IS MADE FINAL. 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 extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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