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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 25, 2026, has been entered.
Response to Arguments
Applicant’s arguments are moot in view of the new prior art cited below. Those arguments not rendered moot are responded to below.
In response to Applicant’s arguments, the examiner applies: Gill et al., “Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease,” BLOOD, 22 OCTOBER 2015 x VOLUME 126, NUMBER 17.
Gill teaches: “rVWF was evaluated for treatment of bleeds in severe VWD. Bleeding episodes were treated with an initial 40 to 60 IU/kg VWF:RCo rVWF for minor to moderate bleeds such as epistaxis, oral bleeding, or menorrhagia and up to 80 IU/kg VWF:RCo for major bleeds, which included bleeds such as severe or refractory epistaxis or menorrhagia, gastrointestinal bleeding, central nervous system trauma, hemarthrosis, or posttraumatic hemorrhage.” See p240. Further, in major bleeding episodes subsequent doses were administered every 8 to 12 hours for 3 days to maintain trough levels of VWF:Rco > 50 IU/dL and then as deemed necessary for up to 7 days. See p2041, 2nd par.
Thus, Gill teaches administration of doses as frequent as every 8 hours for three days and then for up to 7 days. This was treatment during a major bleeding episode. Menorrhagia is a source of minor and major bleeds. This is thought to include on-demand treatment.
A combination of prior art teaches treatment of the VWF, including menorrhagia bleeding episodes that are minor and major with rVWF administered as frequently as every 8 hours for 3 days and then treatment continues for up to 7 days as needed to maintain levels. This is an on-demand treatment, which is also taught as common for coagulation disorders.
A § 112 indefiniteness rejection is set forth because it is not clear what doses are second “doses” and what doses constitute a third dose, e.g. It is not clear when the plurality of second doses shifts to being considered a third dose. It is also not clear if the third dose must also be given within the claimed 8 to 12 hours or if the timing requirement is merely being applied to the timing for “second” doses. Further, it is not clear nor does it appear required for the second doses to be of a different amount or duration as a third dose.
The instant claims include administering a first dose and 12 hours later administering a second dose. Further, while a third dose can be administered, the third dose can be administered at any period after the second doses are administered. For example, claim 17 is directed to administering a third dose for the remaining duration of the bleeding episode. This could be a once daily dose or a dose that is administered every 8 hours. There is no limitation specifying timing for a third dose.
Applicant has added experiencing abnormal uterine bleeding and on-demand treatment to the claims. Further, the claims now recite a second dose every 8 to 12 hours for up to 3 days.
The examiner notes that the Specification refers to menorrhagia as abnormal uterine bleeding. In view of Applicant’s arguments, Federici is no longer applied. Federici was the tertiary reference cited in the previous Office Action.
Applicant argues that the examiner used hindsight reasoning to pick and choose from the prior art to make the obviousness rejection of record.
The examiner notes that hindsight reconstruction was not necessary nor needed to make the rejections set forth below.
The teachings of Gill are set forth above.
Hemophilia and VWD are each taught to be treated with coagulation factors including rFVIII among others and on-demand treatment is taught to be standard. Scheiflinger is directed towards treating hemophilia and VWD by administering VWF and/or VWF with FVIII. The method is designed to provide replacement for coagulation factors. Scheiflinger teaches on-demand treatment to be common for treating hemophilia, including administration of clotting factors, such as FVIII. See par. 151 and 220. This means that administration of FVIII can be on-demand and can have an effect of mitigating a coagulation disorder. VWD is a coagulation disorder.
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 with a prevalence of up to 100% of subjects with VWD. Scheiflinger teaches treating VWD and/or hemophilia by administering coagulation factors, including rVWF and rFVIII. Further, Scheiflinger teaches treatment can be administered twice a day. This includes every 12 hours, e.g. See par. 215. Further, common treatments for hemophilia include on-demand administration of clotting factors such as FVIII. See par. 151. As set forth previously, the dosage claimed includes substantial overlap with the claimed dosage and includes a range of 30-130 IU/kg. See par. 207.
Thus, the prior art teaches treating the claimed subject with the claimed agents at the claimed concentrations. Gill teaches treatment for the claimed periods of time. This includes treatment for minor and major menorrhagia bleeding episodes in VWD, which is defined as an abnormal uterine bleeding. As such, a rejection is set forth below.
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 17, 18, 25, 26, 32, 33, 40, 46 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. Claim 17 requires administration for the remaining duration of the bleeding episode. Claim 17 depends indirectly from claim 1, which limits treatment to up to 3 days. Similarly, claim 18 provides for administration for no more than 7 days. It is not clear if the up to 3 days refers only to doses referred to as “second doses” or if the administration of doses includes all doses. Further, it is not clear how to determine which plurality of second doses count as second doses and when they the plurality of doses become “a third dose.” It is also not clear if the third dose must also be given within the claimed 8 to 12 hours or if that is merely to be applied to the timing for “second” doses. Further, it is not clear if treatment is limited to 3 days for all doses or if only those doses considered “second doses” can be administered for up to 3 days and then a third dose can be administered for “about 7 days” as is also claimed.
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 Gill et al., “Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease,” BLOOD, 22 OCTOBER 2015 x VOLUME 126, NUMBER 17.
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 does not teach each dosage regimen with specificity.
Gill teaches: “rVWF was evaluated for treatment of bleeds in severe VWD. Bleeding episodes were treated with an initial 40 to 60 IU/kg VWF:RCo rVWF for minor to moderate bleeds such as epistaxis, oral bleeding, or menorrhagia and up to 80 IU/kg VWF:RCo for major bleeds, which included bleeds such as severe or refractory epistaxis or menorrhagia, gastrointestinal bleeding, central nervous system trauma, hemarthrosis, or posttraumatic hemorrhage.” See p240. Further, in major bleeding episodes subsequent doses were administered every 8 to 12 hours for 3 days to maintain trough levels of VWF:Rco > 50 IU/dL and then as deemed necessary for up to 7 days. See p2041, 2nd par.
Thus, Gill teaches administration of doses as frequent as every 8 hours for three days and then for up to 7 days. This was treatment during a major bleeding episode. Menorrhagia is a source of minor and major bleeds.
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 Gill 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, VWD is the most common inherited bleeding disorder and menorrhagia is the most common symptom of women with VWD. The prevalence is up to 100% of subjects. 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 Gill each teach treating menorrhagia in subjects with severe VWD by administering rVWF and rFVIII. Treatment includes administration every 8 hours for 3 days and then treatment can continue when necessary for up to 7 days. 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).
A showing of unexpected results has not been shown or alleged. As such, the examiner has determined that a prima facie showing is established in view of the cited prior art.
Conclusion
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 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy 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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