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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/10/2026 has been entered.
Claim Status
Claims 1-24 are pending. Claim 24 has been amended. Claims 1-4, 6, 9, 12, 14, 17, 19 and 22-24 are being examined in this application. In the response to the restriction requirement, Applicants elected no FVIII is administered after the surgical procedure, and major surgery. Claims 5, 7-8, 10-11, 13, 15-16, 18 and 20-21 are withdrawn as being drawn to a nonelected species.
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.
This rejection is maintained.
Claims 1-4, 6, 9, 12, 14, 17, 19 and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Hauser et al. (EP1593390) in view of Kronthaler et al. (WO 2008/151817).
Hauser et al. teach a method of use of plasma protein concentrates containing VWF with a high proportion of high molecular weight multimers for the preparation of a pharmaceutical composition to prevent a bleeding diathesis and to reduce pre-, peri- and postoperative blood loss in acquired Von Willebrand syndromes preferentially in cardiovascular diseases requiring surgical procedures (claim 1; para [0008]).
Please note that the surgical procedures described by Hauser et al. (i.e. cardiovascular diseases requiring surgical procedures) are considered major surgical procedures.
Hauser et al. do not teach: 1) the VWF is recombinant; 2) administering 40-60 IU/kg rVWF 12-24 hours before the surgical procedure; and 3) administering 5-90 IU/kg VWF one hour prior to the surgical procedure.
Kronthaler et al. teach that the most frequent inherited bleeding disorder in humans is von Willebrand's disease (VWD), which can be treated by replacement therapy with concentrates containing VWF of plasmatic or recombinant origin (page 2, lines 5-7).
Kronthaler et al. further teach that the method comprises administering to said individual an efficient amount pharmaceutical composition comprising VWF or VWF in combination with FVlll (page 18, lines 18-20).
Kronthaler et al. also teach that the concentration of VWF can be equal to or more than 150 U (VWF:Ag)/ ml preferentially equal to or more 450 U (VWF:Ag)/ ml, most preferentially equal to or more than 1500 U (VWF:Ag)/ ml. A typical dose could be equal to or more than 225 U (VWF:Ag)/ kg or equal to or more than 75 U (VWF:Ag)/ kg, or equal to or more 15 U (VWF:Ag)/ kg (page 9, lines 1-6).
It would have been obvious to one of ordinary skill in the art to substitute the plasma derived VWF of Hauser et al. with the recombinant VWF of Kronthaler et al. because both references teach treating von Willebrand's disease (VWD) with concentrates containing VWF, wherein the VWF is of plasmatic or recombinant origin (taught by Kronthaler et al.).
Furthermore, it would have been obvious to one of ordinary skill in the art to discover efficient amounts of VWF by normal optimization procedures known in the pharmaceutical art because Kronthaler et al. teach administering an efficient amount of a pharmaceutical composition comprising VWF, and further teach various concentrations of VWF.
Moreover, it would have been obvious, with a reasonable expectation of success, to discover the time of administration of VWF by normal optimization procedures known in the pharmaceutical art because Hauser et al. teach that concentrates containing VWF are used to prevent (thus administered before a surgical procedure) a bleeding diathesis and to reduce pre-, peri- and postoperative blood loss in acquired Von Willebrand syndromes preferentially in cardiovascular diseases requiring surgical procedures.
With respect to claims 22-24, as discussed above, Hauser et al. teach that the plasma protein concentrates contain VWF with a high proportion of high molecular weight multimers (claim 1; para [0008]).
The MPEP 2144.05 A states that “[G]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997)”.
Since Applicant has not disclosed that the specific limitations recited in the instant claims are for any particular purpose or solve any stated problem, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum number of subunits of the multimeric VWF, as well as the optimum amount of VWF multimers or ultra-large multimers by normal optimization procedures known in the pharmaceutical art.
The skilled artisan would have had a reasonable expectation of success because Hauser et al. teach that the plasma protein concentrates contain VWF with a high proportion of high molecular weight multimers.
Response to Arguments
The arguments filed on 2/10/2026 have been fully considered but are not found persuasive.
Applicants argue that:
1) The cited art does not teach all the limitations of Claim 1;
2) Whereas the claimed invention recites pretreatment with VWF without FVIII, the cited art teaches away from this limitation and instead suggests that effective treatment of VWD requires administration of both VWF and FVIII;
3) A person of skill in the art would have been dissuaded from substituting plasma-derived VWF with rVWF based on the cited art, even if they had known that rVWF contains L/UL multimers;
4) Any inherent properties of rVWF would not make it obvious to use rVWF in a new method comprising pretreatment of patients with severe VWD prior to surgery;
5) The Examiner's stated rationale for combining Hauser with Kronthaler relies on impermissible hindsight;
6) The Claimed Methods are Additionally Non-Obvious In View of Superior and Unexpected Results.
Applicant’s arguments are not persuasive.
In response to Applicant's piecemeal analysis of the references, it has been held that one cannot show non-obviousness by attacking references individually where, as here, the rejections are based on combinations of references. In re Keller, 208 USPQ 871 (CCPA 1981).
It is clear from the teachings of Hauser et al. that both VWS and VWD are treated by administering VWF with a high proportion of high molecular weight multimers (para [0004]).
Specifically, Hauser et al. teach that “[D]efects in VWF are causal to Von Willebrand disease (VWD), which is characterized by a more or less pronounced bleeding phenotype. VWD type 3 is the most severe form in which VWF is completely missing, VWD type 1 relates to a quantitative loss of VWF and its phenotype can be very mild. VWD type 2 relates to qualitative defects of VWF and can be as severe as VWD type 3. VWD type 2 has many sub forms some of them being associated with the loss or the decrease of high molecular weight multimers. Von Willebrand syndrome type 2a (VWS-2a) is characterized by a loss of both intermediate and large multimers. VWS-2B is characterized by a loss of highest-molecular-weight multimers” (para [0003]).
With respect to 2), the MPEP 2123 states that “[D]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have "relatively acceptable dimensional stability" and "some degree of flexibility," but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since "Gurley asserted no discovery beyond what was known in the art." Id. at 554, 31 USPQ2d at 1132.). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004)”.
In the instant case, Kronthaler does not discredit the administration of VWF alone. Furthermore, Kronthaler clearly teaches administering VWF without FVIII, and further teach that FVlll:C plasma level increase above baseline was surprisingly about two-fold higher in the group treated with the "monomer" preparation of Haemate® P as compared to the group treated with the "multimer" preparation (page 44, last para).
Therefore, Kronthaler et al. do not discredit using the "multimer" preparation, which also increased, albeit to a lesser extent, FVlll:C plasma level.
With respect to 3) and 5), Kronthaler et al. teach a composition suitable for extravascular administration in the therapy of von Willebrand disease (VWD) and/or hemophilia A comprising purified von Willebrand factor (VWF), wherein von Willebrand factor is derived from human plasma or is produced recombinantly, and further teach the compositions consist of either predominantly small or large multimers, and Kahlon et al. teach that there exists an association between elevated plasma VWF/FVIII levels and an increased tendency towards postoperative thrombotic events.
Therefore, it would have been obvious to the skilled artisan to substitute the plasma derived VWF of Hauser et al. with the recombinant VWF of Kronthaler et al.
Furthermore, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success to measure the subject’s FVIII levels and compare to VWF levels in order to determine whether VWF/FVIII levels are elevated or not prior to the surgical procedure.
With respect to 4) and 6), Kronthaler et al. clearly teach rVWF. The claimed unexpected results are inherent to UL multimers, which are present in the rVWF taught by Kronthaler et al.
Furthermore, the MPEP 2144.05 A states that “[G]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical”. In the instant case, Kronthaler et al. teach that “[t]he concentration of VWF can be equal to or more than 150 U (VWF:Ag)/ ml preferentially equal to or more 450 U (VWF:Ag)/ ml, most preferentially equal to or more than 1500 U (VWF:Ag)/ ml. A typical dose could be equal to or more than 225 U (VWF:Ag)/ kg or equal to or more than 75 U (VWF:Ag)/ kg, or equal to or more 15 U (VWF:Ag)/ kg”, and Hauser et al. teach that concentrates containing VWF are used to prevent (i.e. are administered before a surgical procedure) a bleeding diathesis and to reduce pre-, peri- and postoperative blood loss in acquired Von Willebrand syndromes preferentially in cardiovascular diseases requiring surgical procedures.
Therefore, the skilled artisan would have been motivated, with a reasonable expectation of success, to discover efficient amounts of VWF and the time of administration of VWF by normal optimization procedures known in the pharmaceutical art.
Moreover, it is noted that a comparison of rVWF and a composition comprising both pdVWF and FVIII (i.e. Humate-P, Wilfactin and Wilate) is not a proper comparison. As discussed in previous Office actions, Applicant should compare pdVWF alone to rVWF alone or compare a composition comprising pdVWF and FVIII, and a composition comprising rVWF and FVIII, because the alleged unexpected fewer infusions might be due to the absence or presence of FVII.
For the reasons stated above, the rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
This rejection is maintained.
Claims 1-4, 6, 9, 12, 14, 17, 19 and 22-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-44 and 47 of copending Application No. 17/545870 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because they relate to the same method.
With respect to claims 1 and 22-23, ‘870 teaches a method for pre-treatment of a subject with severe von Willebrand disease (VWD) prior to a surgical procedure, wherein said pre-treatment comprises the following steps:(i) administering 40-60 IU/kg of recombinant Von Willebrand Factor (rVWF) to said subject between 12 hours and 24 hours prior to said surgical procedure, wherein Factor VIII (FVIII) is not administered with the rVWF prior to the surgical procedure, wherein the rVWF comprises ultra-large multimers (ULMs), wherein the ULMs comprise over 40 subunits and are at least 10,000 kDa;(ii) measuring the subject's FVIII:C level within 3 hours prior to said procedure; and (iii) administering 5-90 IU/kg rVWF to said subject within 1 hour prior to said surgical procedure (claim 23).
‘988 further teaches that the rVWF comprises ultra-large multimers (ULMs), wherein the ULMs are at least 10,000 kDa (claim 23).
With respect to claim 2, ‘870 teaches further administering 5-90 IU/kg rVWF (claim 28)
With respect to claim 3, ‘870 teaches that FVIII is not administered after said surgical procedure (claim 24).
With respect to claim 4, ‘870 teaches that the surgical procedure is selected from the group consisting of major surgery, minor surgery, and oral surgery (claim 25).
With respect to claim 6, ‘870 teaches administering 45-60 IU/kg rVWF between 12 hours and 24 hours prior to a major surgical procedure (claim 27).
With respect to claim 9, ‘870 teaches administering 15-90 IU/kg rVWF 1 hour prior to a major surgical procedure (claim 30).
With respect to claim 12, ‘870 teaches that the subject is administered 70-220 IU/kg rVWF after said surgical procedure (claim 33).
With respect to claim 14, ‘870 teaches that the subject is administered 150-220 IU/kg rVWF after said surgical procedure and said surgical procedure is a major surgical procedure (claim 35).
With respect to claim 17, ‘870 teaches that the subject is administered a total dosage of 220-320 IU/kg rVWF and said surgical procedure is a major surgical procedure (claim 38).
With respect to claim 19, ‘870 teaches that the surgical procedure is a major surgical procedure and said pre-treatment comprises administering at least two approximately equal doses of rVWF prior to the surgical procedure (claim 40).
With respect to claim 24, ‘870 teaches that the rVWF comprises a percentage of high molecular weight (HMW) rVWF multimers, wherein the HMW rVWF multimers comprises at least 10% rVWF decamers or higher order multimers (claim 47).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
In the response filed on 2/10/2026, Applicants requested the double patenting rejections to be held in abeyance.
For this reason, the rejection above is maintained.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SERGIO COFFA whose telephone number is (571)270-3022. The examiner can normally be reached M-F: 6AM-4PM.
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/SERGIO COFFA Ph.D./
Primary Examiner
Art Unit 1658
/SERGIO COFFA/Primary Examiner, Art Unit 1658
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