DETAILED CORRESPONDENCE
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s preliminary amendments received August 22, 2024 are acknowledged.
Claims 1-26 have been canceled.
Claims 27-46 have been added.
Claims 27-46 are pending in the instant application.
Information Disclosure Statement
The IDS forms received 1/5/2024 and 8/23/2024 are acknowledged and the references cited therein have been considered.
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 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.
Claim Rejections - 35 USC § 103
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.
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 27-34 and 36-46 are rejected under 35 U.S.C. 103 as being unpatentable over Nieswandt et al. (US 2008/0254039) in view of Panousis et al. (WO 2013/014092) and in view of Mannesse et al. (WO 2007/073186).
Nieswandt et al. disclose that compositions comprising factor XII inhibitors are to be used to treat conditions characterized by thrombus formation (see entire document, particularly the abstract, paragraphs [0002], and the claims). Thrombotic conditions treated include hereditary angioedema (see particularly paragraph [0011]) and the compositions used include an anti-Factor XII antibody and the protease inhibitor C1 inhibitor (see particularly the abstract, paragraphs [0008-0016] and claims 17-31, particularly claim 24). Intravenous administration is disclosed (see particularly paragraph [0018]). Antibodies contain the half-life enhancing polypeptide known as “Fc” which is joined to the variable domains by the hinge region which is a flexible polypeptide sequence that acts as a linker between the antigen binding and Fc domains. It should be noted that the instant claims recite that the active agents are administered either at the same time (claim 37) or sequentially (claims 38 and 39), with either agent being recited as administered first (and as such there is no preferred order of administration as all are claimed). Note that term “sequentially” simply indicates that an interval of time has passed, with dependent claims such as 39 providing guidance as to the time interval between “sequential” administrations. Thus, all that is required of independent claim 27 is that both agents are administered to the patient as all possible orders (i.e. together, A first, B first) as all possible time intervals are encompassed by the inventions as presently recited in the dependent claims. Further, it should be pointed out that Nieswandt et al. discuss administration to patients having clinically defined diseases and disorders, and given that these diseases (and indeed almost all clinical diseases) are diagnosed after the patient displays the clinical signs and symptoms of the disease in question, administration necessarily occurs after development of the disorder. Administration of FXII inhibitors is disclosed as being performed via a variety of routes and doses including continuous intravenous infusion (see particularly paragraphs [0017-0020]), and that inhibition of FXII inhibits thrombosis without inhibiting hemostasis such that patients treated with FXII inhibitors are not at an increased risk of bleeding/hemorrhage (see particularly paragraphs [0006] and [0008]).
These teachings differ from the instant claimed invention in that even though the combined administration of an anti-FXII antibody and a C1-inhibitor to treat angioedema is disclosed by Nieswandt et al., the anti-FXII antibody is not disclosed as being VR115 and the source and dosing of C1 inhibitor is not specified.
Panousis et al. disclose the 3F7 anti-FXII antibody (i.e. VH of instant SEQ ID NO:6 and VL of instant SEQ ID NO:7 as evidenced by Table 1 of the instant specification) and its improved, affinity matured variant VR115, and the administration of such antibodies to treat thrombotic conditions including hereditary angioedema (see entire document, particularly the abstract, pages 9-11, Tables 1 and 6, example 2 and the claims). 3F7 and its variants are disclosed as comprising the advantage of having high inhibitory activity, not increasing bleeding risk, being non-immunogenic, and as having a long half-life as compared to prior art anti-FXII antibodies (see most particularly page 7). It should be pointed out that as demonstrated in Table 6 on page 51, the VR115 variant had the greatest fold improvement in binding affinity as compared to the parental 3F7 antibody. IgG is disclosed as being the preferred isotype for anti-FXII antibodies (see particularly page 21 as well as example 3). Antibody doses which lie within the ranges recited in the instant claims, including the use of multiple doses are disclosed (see particularly pages 34-35) and also that it is routine for artisans to determine effective dosing strategies as no undue experimentation is required (see especially lines 22-26 of page 34).
Mannesse et al. disclose the production of recombinant human C1 inhibitor (C1-INH) and its administration to treat thrombotic conditions (see entire document, particularly the abstract, claims and pages 1 and 11). Notably, they disclose that their C1-INH has the advantageous property of working better than plasma-derived C1-INH due to changes in glycosylation which result in a greatly expanded window of therapeutic efficacy (see particularly pages 2 and 7-11). Notably, administration is disclosed as taking place between immediately after and up to 18 hours post traumatic event (see for example pages 10 and 11). Therapeutic doses which lie within those recited in the instant claims are taught as being effective (see particularly page 16), and it is also taught that practitioners will arrive at suitable administration protocols using routine optimization (see particularly page 15). Administration via a variety of routes including intravenous and subcutaneous are disclosed (see particularly page 15).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the instant invention was made to substitute the anti-FXII antibodies used in the methods of Nieswandt et al. with those of Panousis et al. when practicing methods of treating thrombotic conditions such as hereditary angioedema. The ordinary artisan would have been motivated to do so in order to gain the advantages of high activity, low bleeding risk, non-immunogenicity, and long half-life as compared to other anti-FXII antibodies as taught by Panousis et al. In particular, artisans would have been motivated to select the improved VR115 antibody as it binds antigen with the greatest affinity of those taught by Panousis et al.
It would have been further obvious to a person of ordinary skill in the art at the time the instant application was filed that the C1-INH of Mannesse et al. could be used in the methods of Nieswandt et al. The ordinary artisan would have been motivated to do so in order to gain the advantage of an increased window of therapeutic activity post-injury for the C1-INH of Mannesse et al. as compared to other forms known in the art as taught by Mannesse et al. Such an increased window of efficacy would allow for later administration something that is clinically useful as patients who develop for example stroke or myocardial infarction typically need to be transported to a hospital to begin treatment such that it is difficult for an artisan to administer the drug immediately after the clinical insult occurs. Also, it should be appreciated that claim language such as “up to 10 days after” is a range that encompasses all times from immediately following the insult to 240 hours later, and therefore any teaching of immediate administration would necessarily lie within such a range.
It should be noted that the times and doses presented in the instant claimed treatment protocol are broad and that the cited prior art clearly indicates that identifying doses and times can be done by routine optimization. Indeed, the courts have long ruled that "[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). Also note that since the drugs in use are taught for treating thrombotic conditions, determining an optimal dosing protocol is optimization of a results effective variable wherein the variable is the dose and time and the result is the clinical condition of the patient. It should be noted that the instant application does not have data from a working example supporting the invention as presently claimed and that there is no evidence that the claimed doses and time intervals were arrived at using anything other than routine optimization.
Claims 27-34 and 36-46 are rejected under 35 U.S.C. 103 as being unpatentable over Nieswandt et al. (US 2008/0254039) in view of Panousis et al. (WO 2013/014092) and in view of Gower et al.
Nieswandt et al. disclose that compositions comprising factor XII inhibitors are to be used to treat conditions characterized by thrombus formation (see entire document, particularly the abstract, paragraphs [0002], and the claims). Thrombotic conditions treated include hereditary angioedema (see particularly paragraph [0011]) and the compositions used include an anti-Factor XII antibody and the protease inhibitor C1 inhibitor (see particularly the abstract, paragraphs [0008-0016] and claims 17-31, particularly claim 24). Intravenous administration is disclosed (see particularly paragraph [0018]). Antibodies contain the half-life enhancing polypeptide known as “Fc” which is joined to the variable domains by the hinge region which is a flexible polypeptide sequence that acts as a linker between the antigen binding and Fc domains. It should be noted that the instant claims recite that the active agents are administered either at the same time (claim 37) or sequentially (claims 38 and 39), with either agent being recited as administered first (and as such there is no preferred order of administration as all are claimed). Note that term “sequentially” simply indicates that an interval of time has passed, with dependent claims such as 39 providing guidance as to the time interval between “sequential” administrations. Thus, all that is required of independent claim 27 is that both agents are administered to the patient as all possible orders (i.e. together, A first, B first) as all possible time intervals are encompassed by the inventions as presently recited in the dependent claims. Further, it should be pointed out that Nieswandt et al. discuss administration to patients having clinically defined diseases and disorders, and given that these diseases (and indeed almost all clinical diseases) are diagnosed after the patient displays the clinical signs and symptoms of the disease in question, administration necessarily occurs after development of the disorder. Administration of FXII inhibitors is disclosed as being performed via a variety of routes and doses including continuous intravenous infusion (see particularly paragraphs [0017-0020]), and that inhibition of FXII inhibits thrombosis without inhibiting hemostasis such that patients treated with FXII inhibitors are not at an increased risk of bleeding/hemorrhage (see particularly paragraphs [0006] and [0008]).
These teachings differ from the instant claimed invention in that even though the combined administration of an anti-FXII antibody and a C1-inhibitor to treat angioedema is disclosed by Nieswandt et al., the anti-FXII antibody is not disclosed as being VR115 and the source and dosing of C1 inhibitor is not specified.
Panousis et al. disclose the 3F7 anti-FXII antibody (i.e. VH of instant SEQ ID NO:6 and VL of instant SEQ ID NO:7 as evidenced by Table 1 of the instant specification) and its improved, affinity matured variant VR115, and the administration of such antibodies to treat thrombotic conditions including hereditary angioedema (see entire document, particularly the abstract, pages 9-11, Tables 1 and 6, example 2 and the claims). 3F7 and its variants are disclosed as comprising the advantage of having high inhibitory activity, not increasing bleeding risk, being non-immunogenic, and as having a long half-life as compared to prior art anti-FXII antibodies (see most particularly page 7). It should be pointed out that as demonstrated in Table 6 on page 51, the VR115 variant had the greatest fold improvement in binding affinity as compared to the parental 3F7 antibody. IgG is disclosed as being the preferred isotype for anti-FXII antibodies (see particularly page 21 as well as example 3). Antibody doses which lie within the ranges recited in the instant claims, including the use of multiple doses are disclosed (see particularly pages 34-35) and also that it is routine for artisans to determine effective dosing strategies as no undue experimentation is required (see especially lines 22-26 of page 34).
Gower et al. disclose that hereditary angioedema is an autosomal dominant disease caused by a deficiency of C1 esterase inhibitor, and that it is clinically treated by administration of exogenous C1 esterase inhibitor (i.e. C1-INH, see entire document, particularly the abstract and page S9). It is disclosed that exogenous C1-INH sourced from human plasma is commercially available and has been granted government regulatory approval in many countries for the treatment of hereditary angioedema (see particularly pages S14 and S15). Notably, administration of C1-INH is suitable both for treatment of acute incidents as well as for prophylactic therapy (see particularly Table 1 as well as page S12). The manifestations and severity of hereditary angioedema are highly variable and thus Gower et al. teach that individualized care is required to best meet the needs of the patient, and that on-demand therapy for attacks with C1-INH is often used (see particularly the abstract, the paragraph spanning pages S11 and S12, and pages S15 and s19).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the instant invention was made to substitute the anti-FXII antibodies used in the methods of Nieswandt et al. with those of Panousis et al. when practicing methods of treating thrombotic conditions such as hereditary angioedema. The ordinary artisan would have been motivated to do so in order to gain the advantages of high activity, low bleeding risk, non-immunogenicity, and long half-life as compared to other anti-FXII antibodies as taught by Panousis et al. In particular, artisans would have been motivated to select the improved VR115 antibody as it binds antigen with the greatest affinity of those taught by Panousis et al.
It would have been further obvious to a person of ordinary skill in the art at the time the instant application was filed that the C1-INH of Gower et al. could be used in the methods of Nieswandt et al. The ordinary artisan would have been motivated to do so as such products are commercially available and have been given regulatory approval for the treatment of hereditary angioedema in many countries as taught by Gower et al. As taught by Gower et al., C1-INH administration is often performed to treat acute symptoms of angioedema even if the patient is also receiving prophylactic therapy. Also, it should be appreciated that claim language such as “up to 10 days after” is a range that encompasses all times from immediately following the insult to 240 hours later, and therefore any teaching of immediate administration would necessarily lie within such a range.
It should be noted that the times and doses presented in the instant claimed treatment protocol are broad and that the cited prior art clearly indicates that identifying doses and times can be done by routine optimization. Further, given the clinical heterogeneity in the symptoms and severity of angioedema artisans would expect to need to tailor their treatment protocols to best meet the needs of their patients as is taught by Gower et al. Further, the courts have long ruled that "[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). Also note that since the drugs in use are taught for treating hereditary angioedema, determining an optimal dosing protocol is optimization of a results effective variable wherein the variable is the dose and time and the result is the clinical condition of the patient. It should be noted that the instant application does not have data from a working example supporting the invention as presently claimed and that there is no evidence that the claimed doses and time intervals were arrived at using anything other than routine optimization.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Nieswandt et al. (US 2008/0254039) in view of Panousis et al. (WO 2013/014092) and in view of Mannesse et al. (WO 2007/073186) as applied to claims 27-34 and 36-46 above, and further in view of Ballance et al. (WO 01/79271).
The inventions rendered obvious by Nieswandt et al., Panousis et al., and Mannesse et al. (hereafter “the prior art”) have been discussed above, and even though they disclose administration of inhibitory anti-FXII antibodies, they do not disclose such antibodies as being joined to albumin.
Balance et al. disclose methods of making albumin fusion proteins (see entire document, particularly the abstract and claims). Such fusion proteins are disclosed as having the advantages of increased half-life in vivo as well as increased storage lifetimes due to the increased stability of the fusion protein as compared to polypeptide in the absence of albumin (see particularly page 2). Antibodies are disclosed as being a polypeptide to which albumin can be fused to increase its half-life (see particularly claim 8 as well as pages 2, 6, and 9). Such fusion proteins are also disclosed as having peptide linkers between the polypeptide domains (see particularly page 54).
Therefore, it would have been obvious to modify the anti-FXII antibodies used in the methods of the prior art to include an albumin domain. Motivation to do so comes from the fact that antibodies thus modified will enjoy enhanced stability as compared to unmodified antibodies which will increase in vivo half-life and storage life as disclosed by Ballance et al.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Nieswandt et al. (US 2008/0254039) in view of Panousis et al. (WO 2013/014092) and in view of Gower et al. as applied to claims 27-34 and 36-46 above, and further in view of Ballance et al. (WO 01/79271).
The inventions rendered obvious by Nieswandt et al., Panousis et al., and Gower et al. (hereafter “the prior art”) have been discussed above, and even though they disclose administration of inhibitory anti-FXII antibodies, they do not disclose such antibodies as being joined to albumin.
Balance et al. disclose methods of making albumin fusion proteins (see entire document, particularly the abstract and claims). Such fusion proteins are disclosed as having the advantages of increased half-life in vivo as well as increased storage lifetimes due to the increased stability of the fusion protein as compared to polypeptide in the absence of albumin (see particularly page 2). Antibodies are disclosed as being a polypeptide to which albumin can be fused to increase its half-life (see particularly claim 8 as well as pages 2, 6, and 9). Such fusion proteins are also disclosed as having peptide linkers between the polypeptide domains (see particularly page 54).
Therefore, it would have been obvious to modify the anti-FXII antibodies used in the methods of the prior art to include an albumin domain. Motivation to do so comes from the fact that antibodies thus modified will enjoy enhanced stability as compared to unmodified antibodies which will increase in vivo half-life and storage life as disclosed by Ballance et al.
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 §§ 706.02(l)(1) - 706.02(l)(3) 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.
Claims 27-34 and 36-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10,513,560 in view of Gower et al.
The claims of the ‘560 patent recite administering antibodies identified via SEQ ID number that bind to and inhibit the activity of FXII for the purpose of treating hereditary angioedema (see all issued claims). Notably, the antibodies administered as part of such claims comprise the CDRs (see issued claim 12 and Table 1 in column 12) and the complete VH and VL sequences of the VR115 antibody (see issued claim 9) which is an affinity matured version of the parental 3F7 antibody (instant SEQ ID NOs:6 and 7 which are identical to issued SEQ ID NOs:4 and 5 respectively, see claims 2 and 3 in particular). Such antibodies are further recited as being IgG (see for example issued claims 20 and 21). The issued claims differ from the invention as presently claimed in that while the issued claims do recite treating hereditary angioedema by administering anti-FXII antibodies, the issued claims do not further indicate that C1-INH is also to be administered to the same hereditary angioedema patient.
Gower et al. disclose that hereditary angioedema is an autosomal dominant disease caused by a deficiency of C1 esterase inhibitor, and that it is clinically treated by administration of exogenous C1 esterase inhibitor (i.e. C1-INH, see entire document, particularly the abstract and page S9). It is disclosed that exogenous C1-INH sourced from human plasma is commercially available and has been granted government regulatory approval in many countries for the treatment of hereditary angioedema (see particularly pages S14 and S15). Notably, administration of C1-INH is suitable both for treatment of acute incidents as well as for prophylactic therapy (see particularly Table 1 as well as page S12). The manifestations and severity of hereditary angioedema are highly variable and thus Gower et al. teach that individualized care is required to best meet the needs of the patient, and that on-demand therapy for attacks with C1-INH is often used (see particularly the abstract, the paragraph spanning pages S11 and S12, and pages S15 and s19).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the instant application was filed to treat hereditary angioedema by administering both an inhibitory anti-FXII antibody and C1-INH to a patient as each is taught separately for use in treating the same condition. It should be noted that the courts have long ruled that "It is prima facie obvious to combine two compositions (each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Artisans would enjoy a reasonable expectation of success in modifying the issued antibody administration methods to include C1-INH as administration of C1-INH has long been in clinical human use for on-demand/acute and prophylactic treatment of hereditary angioedema as discussed by Gower et al. It is true that the issued claims do not recite any specific doses or times concerning administration, but the courts have long decided "[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). Further, as taught by Gower et al. physicians are well aware of the need to alter treatment protocols to best meet the needs of hereditary angioedema patients and thus routinely engage in such optimization. Further, since the drugs C1-INH and inhibitory anti-FXII antibodies are taught for treating hereditary angioedema, determining an optimal dosing protocol is optimization of a results effective variable wherein the variable is the dose and time and the result is the clinical condition of the patient. It should be noted that the instant application does not have data from a working example supporting the invention as presently claimed and that there is no evidence that the claimed doses and time intervals were arrived at using anything other than routine optimization.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10,513,560 in view of Gower et al. as applied to claims 27-34 and 34-46 above, and further in view of Ballance et al. (WO 01/79271).
The inventions rendered obvious by the issued claims and Gower et al. have been discussed above, and even though they disclose administration of inhibitory anti-FXII antibodies, they do not disclose such antibodies as being joined to albumin.
Balance et al. disclose methods of making albumin fusion proteins (see entire document, particularly the abstract and claims). Such fusion proteins are disclosed as having the advantages of increased half-life in vivo as well as increased storage lifetimes due to the increased stability of the fusion protein as compared to polypeptide in the absence of albumin (see particularly page 2). Antibodies are disclosed as being a polypeptide to which albumin can be fused to increase its half-life (see particularly claim 8 as well as pages 2, 6, and 9). Such fusion proteins are also disclosed as having peptide linkers between the polypeptide domains (see particularly page 54).
Therefore, it would have been obvious to modify the anti-FXII antibodies used in the methods rendered obvious by the combination of the issued claims and Gower et al. to include an albumin domain. Motivation to do so comes from the fact that antibodies thus modified will enjoy enhanced stability as compared to unmodified antibodies which will increase in vivo half-life and storage life as disclosed by Ballance et al.
Claims 27-34 and 36-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 8,715,672 in view of Panousis et al. (WO 2013/014092), in view of Gower et al., and in view of Nieswandt et al. (US 2008/0254039).
The claims of the ‘672 patent recite administering inhibitory antibodies that bind to and inhibit the activity of FXII for the purpose of treating hereditary angioedema (see all issued claims, most particularly claims 3 and 6). Such antibodies are recited as being administered prophylactically (claim 5) and subsequent to an angioedema event (claim 6). The issued claims differ from the invention as presently claimed in that while the issued claims do recite treating hereditary angioedema by administering anti-FXII antibodies, the antibody administered by the issued claims is not required to have the biological sequences as recited in the instant claims and the issued claims do not further indicate that C1-INH is also to be administered to the same hereditary angioedema patient.
Panousis et al. disclose the 3F7 anti-FXII antibody (i.e. VH of instant SEQ ID NO:6 and VL of instant SEQ ID NO:7 as evidenced by Table 1 of the instant specification) and its improved, affinity matured variant VR115, and the administration of such antibodies to treat thrombotic conditions including hereditary angioedema (see entire document, particularly the abstract, pages 9-11, Tables 1 and 6, example 2 and the claims). 3F7 and its variants are disclosed as comprising the advantage of having high inhibitory activity, not increasing bleeding risk, being non-immunogenic, and as having a long half-life as compared to prior art anti-FXII antibodies (see most particularly page 7). It should be pointed out that as demonstrated in Table 6 on page 51, the VR115 variant had the greatest fold improvement in binding affinity as compared to the parental 3F7 antibody. IgG is disclosed as being the preferred isotype for anti-FXII antibodies (see particularly page 21 as well as example 3). Antibody doses which lie within the ranges recited in the instant claims, including the use of multiple doses are disclosed (see particularly pages 34-35) and also that it is routine for artisans to determine effective dosing strategies as no undue experimentation is required (see especially lines 22-26 of page 34).
Gower et al. disclose that hereditary angioedema is an autosomal dominant disease caused by a deficiency of C1 esterase inhibitor, and that it is clinically treated by administration of exogenous C1 esterase inhibitor (i.e. C1-INH, see entire document, particularly the abstract and page S9). It is disclosed that exogenous C1-INH sourced from human plasma is commercially available and has been granted government regulatory approval in many countries for the treatment of hereditary angioedema (see particularly pages S14 and S15). Notably, administration of C1-INH is suitable both for treatment of acute incidents as well as for prophylactic therapy (see particularly Table 1 as well as page S12). The manifestations and severity of hereditary angioedema are highly variable and thus Gower et al. teach that individualized care is required to best meet the needs of the patient, and that on-demand therapy for attacks with C1-INH is often used (see particularly the abstract, the paragraph spanning pages S11 and S12, and pages S15 and s19).
Nieswandt et al. disclose that compositions comprising factor XII inhibitors are to be used to treat conditions characterized by thrombus formation (see entire document, particularly the abstract, paragraphs [0002], and the claims). Thrombotic conditions treated include hereditary angioedema (see particularly paragraph [0011]) and the compositions used include an anti-Factor XII antibody and the protease inhibitor C1 inhibitor (see particularly the abstract, paragraphs [0008-0016] and claims 17-31, particularly claim 24). Intravenous administration is disclosed (see particularly paragraph [0018]). Antibodies contain the half-life enhancing polypeptide known as “Fc” which is joined to the variable domains by the hinge region which is a flexible polypeptide sequence that acts as a linker between the antigen binding and Fc domains. It should be noted that the instant claims recite that the active agents are administered either at the same time (claim 37) or sequentially (claims 38 and 39), with either agent being recited as administered first (and as such there is no preferred order of administration as all are claimed). Note that term “sequentially” simply indicates that an interval of time has passed, with dependent claims such as 39 providing guidance as to the time interval between “sequential” administrations. Thus, all that is required of independent claim 27 is that both agents are administered to the patient as all possible orders (i.e. together, A first, B first) as all possible time intervals are encompassed by the inventions as presently recited in the dependent claims. Further, it should be pointed out that Nieswandt et al. discuss administration to patients having clinically defined diseases and disorders, and given that these diseases (and indeed almost all clinical diseases) are diagnosed after the patient displays the clinical signs and symptoms of the disease in question, administration necessarily occurs after development of the disorder. Administration of FXII inhibitors is disclosed as being performed via a variety of routes and doses including continuous intravenous infusion (see particularly paragraphs [0017-0020]), and that inhibition of FXII inhibits thrombosis without inhibiting hemostasis such that patients treated with FXII inhibitors are not at an increased risk of bleeding/hemorrhage (see particularly paragraphs [0006] and [0008]).
Therefore, it would have been obvious to a person of ordinary skill in the art at the time the instant invention was made to use the anti-FXII antibodies of Panousis et al. in the issued methods of treating hereditary angioedema. The ordinary artisan would have been motivated to do so in order to gain the advantages of high activity, low bleeding risk, non-immunogenicity, and long half-life as compared to other anti-FXII antibodies as taught by Panousis et al. In particular, artisans would have been motivated to select the improved VR115 antibody as it binds antigen with the greatest affinity of those taught by Panousis et al.
Further, it would have been obvious to a person of ordinary skill in the art at the time the instant application was filed to treat hereditary angioedema by administering both an inhibitory anti-FXII antibody and C1-INH to a patient for multiple reasons. First, each is taught separately for use in treating the same condition as shown by the issued claims for the antibody and Gower et al. for C1-INH, and second because Nieswandt et al. explicitly teach that both an anti-Factor XII antibody and the protease inhibitor C1 inhibitor are to be administered for treating angioedema. It should be appreciated that the courts have long ruled that "It is prima facie obvious to combine two compositions (each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Artisans would enjoy a reasonable expectation of success in modifying the issued antibody administration methods to include C1-INH as administration of C1-INH has long been in clinical human use for on-demand/acute and prophylactic treatment of hereditary angioedema as discussed by Gower et al. as well as the fact that both reagents are taught as being administered to the same patient population by Nieswandt et al. It is true that the issued claims do not recite any specific doses or times concerning administration, but the courts have long decided "[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). Further, as taught by Gower et al. as well as Panousis et al., physicians are well aware of the need to alter treatment protocols to best meet the needs of hereditary angioedema patients and thus routinely engage in such optimization. Further, since the drugs C1-INH and inhibitory anti-FXII antibodies are taught for treating hereditary angioedema, determining an optimal dosing protocol is optimization of a results effective variable wherein the variable is the dose and time and the result is the clinical condition of the patient. It should be noted that the instant application does not have data from a working example supporting the invention as presently claimed and that there is no evidence that the claimed doses and time intervals were arrived at using anything other than routine optimization.
It should be noted that while the instant application has no inventors in common with the ‘672 patent, both the instant application and issued patent appear to be commonly assigned to CSL Behring GmbH. If such information is incorrect, applicant is invited to submit evidence concerning the correct assignment as part of any rebuttal to this rejection.
Claim 35 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 8,715,672 in view of Panousis et al. (WO 2013/014092), in view of Gower et al., and in view of Nieswandt et al. (US 2008/0254039) as applied to claims 27-34 and 36-46 above, and further in view of Ballance et al. (WO 01/79271).
The inventions rendered obvious by the combination of the issued claims and the prior art have been discussed above, and even though they disclose administration of inhibitory anti-FXII antibodies, they do not disclose such antibodies as being joined to albumin.
Balance et al. disclose methods of making albumin fusion proteins (see entire document, particularly the abstract and claims). Such fusion proteins are disclosed as having the advantages of increased half-life in vivo as well as increased storage lifetimes due to the increased stability of the fusion protein as compared to polypeptide in the absence of albumin (see particularly page 2). Antibodies are disclosed as being a polypeptide to which albumin can be fused to increase its half-life (see particularly claim 8 as well as pages 2, 6, and 9). Such fusion proteins are also disclosed as having peptide linkers between the polypeptide domains (see particularly page 54).
Therefore, it would have been obvious to modify the anti-FXII antibodies used in the methods rendered obvious by the combination of the patented claims and cited art to include an albumin domain. Motivation to do so comes from the fact that antibodies thus modified will enjoy enhanced stability as compared to unmodified antibodies which will increase in vivo half-life and storage life as disclosed by Ballance et al.
No claims are allowable.
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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641
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