Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Applicant’s 3-9-26 election, without traverse, of the species of subject in need of reducing binding of CD40L to CD40R which is "an autoimmune disease" patient is acknowledged.
Upon reconsideration, the election of species requirement has been extended to include the species of subject in need of reducing binding of CD40L to CD40R which is "a transplant recipient".
Claims 122-142 are pending and under examination as they read on the species of subject in need of reducing binding of CD40L to CD40R which is "an autoimmune disease" patient or which is "a transplant recipient" patient.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 123 is 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.
While the instant specification indicates that SEQ ID NO: 11 = “IEV” and that SEQ ID NO: 16 = “(XDE)nYSI,” or perhaps just “YSI” (??), but neither of these tripeptides can used in the sequence listing and thus according to the sequence listing XML filed 4-3-23 SEQ ID NOs: 11 and 16 are displayed as “000”. Thus, it would be unclear to the ordinarily skilled artisan what exactly is being claimed. One way applicant could overcome this rejection is by replacing SEQ ID NOs: 11 and 16 with the appropriate amino acid sequence, e.g., replacing SEQ ID NO: 11 with the sequence “IEV.”
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 122-133 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of 1-7, 26, 32-34, 36, 38, 39 of U.S. Patent No. 11555062. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims.
For example, reference claim 2 drawn to “[a] method comprising administering an effective amount of a composition comprising a Tn3 scaffold to a subject with an autoimmune disease, wherein the Tn3 scaffold comprises at least one CD40L-specific monomer subunit, wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 4, the BC loop comprises a sequence selected from the group consisting of SEQ ID NOS: 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 168, the CD loop comprises SEQ ID NO: 6, the DE loop comprises a sequence selected from the group consisting of SEQ ID NOs: 94, 95, 96, 97, 98, and 169, the EF loop comprises SEQ ID NO: 8, and the FG loop comprises a sequence selected from the group consisting of SEQ ID NOS: 9, 99, 139, and 170,
wherein the autoimmune disease is selected from the group consisting of alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune diseases of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis and orchitis, Sjogren's syndrome, atherosclerosis, a retinopathy, retrolental fibroplasia, age-related macular degeneration, neovascular glaucoma, hemangiomas, Grave's disease, sepsis, arthritis, peritonitis, Crohn's disease, reperfusion injury, septicemia, endotoxic shock, cystic fibrosis, endocarditis, psoriasis, anaphylactic shock, organ ischemia, spinal cord injury and allograft rejection, autoimmune thrombocytopenia, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, glomerulonephritis, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA neuropathy, lichen planus, Meniere's disease, mixed connective tissue disease, multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychrondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, Raynaud's phenomenon, Reiter's syndrome, sarcoidosis, scleroderma, stiff-man syndrome, systemic lupus erythematosus, lupus erythematosus, takayasu arteritis, temporal arteritis giant cell arteritis, ulcerative colitis, uveitis, vasculitides, vitiligo, and Wegener's granulomatosis;
as well as reference dependent claims 3-7 which recite:
“3. The method of claim 2, wherein the autoimmune disease is systemic lupus erythematosus.
4. The method of claim 2, wherein the autoimmune disease is arthritis.
5. The method of claim 4, wherein the arthritis is juvenile arthritis.
6. The method of claim 4, wherein the arthritis is rheumatoid arthritis.
7. The method of claim 2, wherein the autoimmune disease is Sjogren's syndrome,”
are sufficient to anticipate instant claims 122 and 127-133.
Likewise, reference claim 24 anticipates instant claim 123;
reference claim 31 anticipates instant claim 124;
reference claim 32 anticipates instant claim 125; and
reference claim 33 anticipates instant claim 126.
In conclusion, claims 122-133 are rejected on the ground of nonstatutory double patenting.
Claims 122-127, 134, 136-139, 141 and 142 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 34 and 37-39 of U.S. Patent No. 11555062 in view of Kenyon et al. (Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8132-7, cited herewith).
Reference claim 34 recites,
“[a] method, comprising administering an effective amount of a composition comprising a Tn3 scaffold to a subject with a disorder comprising inflammation, wherein the Tn3 scaffold comprises at least one CD40L-specific monomer subunit, wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 4, the BC loop comprises a sequence selected from the group consisting of SEQ ID NOS: 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 168, the CD loop comprises SEQ ID NO: 6, the DE loop comprises a sequence selected from the group consisting of SEQ ID NOs: 94, 95, 96, 97, 98, and 169, the EF loop comprises SEQ ID NO: 8, and the FG loop comprises a sequence selected from the group consisting of SEQ ID NOS: 9, 99, 139, and 170.”
(emphasis added)
Dependent reference claims 37-39 further specify,
“[t]he method of claim 34, wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, wherein the A beta strand consists of SEQ ID NO:11, the B beta strand consists of SEQ ID NO:12, the C beta strand consists of SEQ ID NO:13 or SEQ ID NO:14, the D beta strand consists of SEQ ID NO:15, the E beta strand consists of SEQ ID NO:16, the F beta strand consists of SEQ ID NO:17, and the G beta strand consists of SEQ ID NO:18, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop consists of SEQ ID NO: 4, the BC loop consists of SEQ ID NO: 86, the CD loop consists of SEQ ID NO: 6, the DE loop consists of SEQ ID NO: 96, the EF loop consists of SEQ ID NO: 8, and the FG loop consists of SEQ ID NO: 139,” and“[t]he method of claim 34, wherein the CD40L-specific monomer subunit comprises SEQ ID NO: 146,” and
“[t]he method of claim 34, wherein the Tn3 scaffold comprises SEQ ID NO: 145,”
respectively.
However, the reference claims do not explicitly recite “A method of reducing binding of CD40 ligand (CD40L) to CD40 receptor comprising administering an effective amount of a composition comprising a Tn3 scaffold to a subject in need, wherein the Tn3 scaffold comprises at least one CD40L- specific monomer subunit, wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 4, the BC loop comprises a sequence selected from the group consisting of SEQ ID NOS: 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 168, the CD loop comprises SEQ ID NO: 6, the DE loop comprises a sequence selected from the group consisting of SEQ ID NOs: 94, 95, 96, 97, 98, and 169,the EF loop comprises SEQ ID NO: 8, and the FG loop comprises a sequence selected from the group consisting of SEQ ID NOS: 9, 99, 139, and 170, ” wherein the subject in need of such reduced binding of CD40L to CD40 is “a transplant recipient.”
Likewise, the reference claims do not explicitly recite “A treatment regimen, comprising administering to a subject in need: a) a Tn3 scaffold that comprises at least one CD40L-specific monomer subunit, wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 4, the BC loop comprises a sequence selected from the group consisting of SEQ ID NOS: 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 168, the CD loop comprises SEQ ID NO: 6, the DE loop comprises a sequence selected from the group consisting of SEQ ID NOs: 94, 95, 96, 97, 98, and 169, the EF loop comprises SEQ ID NO: 8, and the FG loop comprises a sequence selected from the group consisting of SEQ ID NOS: 9, 99, 139, and 170; and b) a conventional therapy selected from the group consisting of: surgery, immunotherapy, chemotherapy, radiation therapy, and a small molecule, wherein the conventional therapy is surgery, and comprises a transplant.”
The Abstract of Kenyon teaches :
“Reported effects of anti-CD154 treatment on autoimmunity, alloreactivity, and inflammatory events mediated by macrophages and endothelial cells indicated that it might be an ideal agent for the prevention of intrahepatic islet allograft failure. This hypothesis was tested in MHC mismatched rhesus monkeys. Transplantation of an adequate number of viable islets resulted in engraftment and insulin independence in six of six recipients treated with anti-CD154 (hu5c8) induction plus monthly maintenance therapy (postoperative day >125, >246, >266, >405, >419, >476)….In striking contrast to all previously tested strategies, transplantation of an adequate number of functional islets under the cover of anti-CD154 (hu5c8) monotherapy consistently allows for allogeneic islet engraftment and long-term insulin independence in this highly relevant preclinical model.”
(emphasis added)
The first paragraph at the Discussion of Kenyon reads as follows:
“Islet cell transplantation offers the promise of a cure for type 1 diabetes, and long-term survival of human islet allografts has now been documented (7). Islet allograft failure in recipients with type 1 diabetes is a complex, multifactorial process involving rejection, recurrence of islet directed autoimmunity, and early loss of islets because of damage mediated by cytokines produced as a result of intrahepatic transplantation (48, 49). In addition, the adverse effects of conventional immunosuppressive drugs, such as steroids, cyclosporin A, and Tacrolimus, contribute to islet loss and nonfunction (37). Blockade of the CD40–CD154 pathway can
prevent allograft rejection (11–16) and graft versus host disease (17–19), can alter the course of autoimmunity (20–29), and can prevent the production of proinflammatory mediators by activated macrophages (32–34) and endothelial cells (35, 36). For these reasons, anti-CD154 (hu5c8) appeared to be an ideal agent for use in islet allotransplantation.
The results of this study clearly demonstrate that monotherapy with anti-CD154 (hu5c8) results in islet engraftment and long-term survival in a highly relevant, pre-clinical allotransplant model….”
(emphasis added)
In the section entitled “Recipient Pancreatectomy and Intrahepatic Islet Cell Transplantation,” Kenyon describes a conventional therapeutic surgical step wherein replacement islet cells and anti-CD154 antibody are simultaneously introduced into the liver of the cynomolgus monkey via an intravenous catheter: “The islets were pelleted and resuspended in 20 ml of transplant media supplemented with 200 units of heparin, and, for recipients treated with anti-CD154 (hu5c8), 20 mg of 5c8 was added. Intrahepatic islet transplantation was accomplished via gravity drainage of islets into a sigmoid or a branch of the left colic vein (draining into the portal vein), through a 24-gauge intravenous catheter,” see page 8133 at col. bridging paragraph.
Given the reference claims drawn to “[a] method, comprising administering an effective amount of a composition comprising a Tn3 scaffold to a subject with a disorder comprising inflammation, wherein the Tn3 scaffold comprises at least one CD40L-specific monomer subunit, wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 4….,” and dependent claims thereof, and further given that blockade of the CD40-CD154 costimulation pathway can prevent production of proinflammatory mediators that play a part in islet allograft rejection (see Kenyon, col. bridging paragraph on page 8132), and the further teachings of Kenyon describing how an anti-CD154 antibody can be used to treat islet allograft rejection (see above), it would have been obvious to one of ordinary skill in the art to extend the reference method comprising administering an effective amount of a composition comprising a Tn3 scaffold to a subject with a disorder comprising inflammation, to the treatment of the inflammation-associated field of transplantation where blocking the binding of CD40L to CD40 has been shown to allow for allogeneic islet engraftment in a highly relevant preclinical model, i.e., the rhesus monkey model system. One reason the one of ordinary skill in the art would have been motivated to practice the method of reference claim 34 in the context of transplantation was because, unlike conventional anti-CD40L antibodies, the Tn3 scaffold of the reference claims would not be expected by the skilled artisan to trigger Fc-mediated complications well known in the prior as described in the instant specification at paragraph 14.
Note that “the Tn3 scaffold [comprising] at least one CD40L-specific monomer subunit” of the reference claims will inherently “reduc[e] binding of CD40 ligand (CD40L) to the CD40 receptor” as recited in the instant claims since this property is inherent to the structure of the Tn3 scaffold of the reference claims.
With respect to the timing of surgical transfer of the islets into the monkey liver, and treatment with the anti-CD154 antibody, Kenyon taught: “The islets were pelleted and resuspended in 20 ml of transplant media supplemented with 200 units of heparin, and, for recipients treated with anti-CD154 (hu5c8), 20 mg of 5c8 was added. Intrahepatic islet transplantation was accomplished via gravity drainage of islets into a sigmoid or a branch of the left colic vein (draining into the portal vein), through a 24-gauge intravenous catheter,” at page 8133, col. bridging paragraph, i.e., Kenyon taught administration of the anti-CD154 antibody in the context of islet transplantation via a surgically placed intravenous catheter. Thus, it would have been obvious to one of ordinary skill in the art that in practicing the method of reference claims 34 and 37-39 for the inhibition of islet allograft rejection that the Tn3 scaffold may be administered either concurrently along with transplantation of the islet allograft, analogous to the teachings of Kenyon, or shortly thereafter, e.g., via a more traditional peripheral intravenous catheter since the target of the administered Tn3 scaffold, CD40L+ cells, are mainly considered to be CD40L+ T-cells found in the blood.
Note that, as described above, the teachings of Kenyon demonstrate that blockade of the CD40-CD154 costimulation pathway can prevent production of proinflammatory mediators that play a part in islet allograft rejection (see Kenyon, col. bridging paragraph on page 8132) but that said inflammatory allograft rejection can be substantially inhibited with an anti-CD154 antibody which blocks the CD40–CD154 pathway (see above), and thus in practicing the obvious method of reference claims 34 and 37-39 modified as described above the ordinarily skilled artisan will necessarily be practicing the method of instant claim 127, and dependent claims thereof. Note further that the “CD40L-specific monomer” of reference claim 38 and the “Tn3 scaffold” of reference claim 39 each comprise particular AB, BC, CD, DE, EF and FG loops recited, e.g., in instant claim 124. Finally, note that “the Tn3 scaffold [comprising] at least one CD40L-specific monomer subunit” of the reference claims will inherently “reduc[e] binding of CD40 ligand (CD40L) to the CD40 receptor” as recited in instant claim 127 and dependent claims thereof since this property is inherent to the structure of the Tn3 scaffold of the reference claims.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 122-127, 134, 136, 137 and 139-142 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 34 and 37-39 of U.S. Patent No. 11555062 in view of Malm et al. (Scandinavian Journal of Immunology 64, 398–403, 2006, cited herewith).
Reference claim 34 recites,
“[a] method, comprising administering an effective amount of a composition comprising a Tn3 scaffold to a subject with a disorder comprising inflammation, wherein the Tn3 scaffold comprises at least one CD40L-specific monomer subunit, wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 4, the BC loop comprises a sequence selected from the group consisting of SEQ ID NOS: 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 168, the CD loop comprises SEQ ID NO: 6, the DE loop comprises a sequence selected from the group consisting of SEQ ID NOs: 94, 95, 96, 97, 98, and 169, the EF loop comprises SEQ ID NO: 8, and the FG loop comprises a sequence selected from the group consisting of SEQ ID NOS: 9, 99, 139, and 170.”
(emphasis added)
Dependent reference claims 37-39 further specify,
“[t]he method of claim 34, wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, wherein the A beta strand consists of SEQ ID NO:11, the B beta strand consists of SEQ ID NO:12, the C beta strand consists of SEQ ID NO:13 or SEQ ID NO:14, the D beta strand consists of SEQ ID NO:15, the E beta strand consists of SEQ ID NO:16, the F beta strand consists of SEQ ID NO:17, and the G beta strand consists of SEQ ID NO:18, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop consists of SEQ ID NO: 4, the BC loop consists of SEQ ID NO: 86, the CD loop consists of SEQ ID NO: 6, the DE loop consists of SEQ ID NO: 96, the EF loop consists of SEQ ID NO: 8, and the FG loop consists of SEQ ID NO: 139,” and“[t]he method of claim 34, wherein the CD40L-specific monomer subunit comprises SEQ ID NO: 146,” and
“[t]he method of claim 34, wherein the Tn3 scaffold comprises SEQ ID NO: 145,”
respectively.
However, the reference claims do not explicitly recite “A treatment regimen, comprising administering to a subject in need: a) a Tn3 scaffold that comprises at least one CD40L-specific monomer subunit, wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 4, the BC loop comprises a sequence selected from the group consisting of SEQ ID NOS: 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 168, the CD loop comprises SEQ ID NO: 6, the DE loop comprises a sequence selected from the group consisting of SEQ ID NOs: 94, 95, 96, 97, 98, and 169, the EF loop comprises SEQ ID NO: 8, and the FG loop comprises a sequence selected from the group consisting of SEQ ID NOS: 9, 99, 139, and 170; and b) a conventional therapy selected from the group consisting of: surgery, immunotherapy, chemotherapy, radiation therapy, and a small molecule, wherein the conventional therapy is immunotherapy and comprises an antibody or portion thereof.”
The Abstract of Malm teaches “…Histological evidences of inflammation and function
were evaluated in grafts that had been functioning for 100 days. Treatment with a combination of all three drugs, or with CTLA4Ig and anti-CD40L, administered four times during the first six postoperative days, resulted in an excellent graft survival. All animals had a graft survival of >100 days (i.e. indefinitely). Mice treated with CTLA4Ig and anti-CD40L all showed well-preserved islets without signs of degeneration or destruction. There were no signs of rejection, as evidenced by the absence of infiltrating lymphocytes. This group had the least amount of rejection/inflammation changes according to ranking of all grafts. In conclusion, a short induction treatment with anti-CD40L and CTLA4Ig totally prevents rejection and preserves
the allogeneic islets transplanted to mice….”
Malm further teaches blockade of the CD28-B7 and the CD40-CD40L pathways via administration of their anti-CD40L and the CTLA4Ig fusion protein was sufficient to not only prevent islet allograft rejection but also to block lymphocyte infiltration of the engrafted islets, i.e., the combination of their anti-CD40L and the CTLA4Ig fusion protein also blocked inflammation (see page 401-402 bridging paragraph).
Given the ability of treatment with anti-CD40L and CTLA4Ig to block inflammation / block rejection and preserve allogeneic islets in a murine model system as taught by Malm, it would have been obvious to one of ordinary skill in the art to extend the reference method comprising administering an effective amount of a composition comprising a Tn3 scaffold to a subject with a disorder comprising inflammation, to the treatment of the inflammation-associated field of allogeneic islet transplantation by modifying the reference method comprising administering a Tn3 scaffold to further include administering the immunotherapeutic CTLA4Ig fusion protein.
One reason that one of ordinary skill in the art would have been motivated to modify the method of reference claim 34 by further administering a CTLA4Ig fusion protein was because, in the context of blocking the CD28-B7 and the CD40-CD40L pathways for the purpose of blocking inflammation / blocking rejection, and preserving allogeneic islets cells, unlike a conventional anti-CD40L antibody, the Tn3 scaffold of the reference claims would not be expected by the skilled artisan to trigger Fc-mediated complications well known in the prior as described in the instant specification at paragraph 14.
Note that, as described above, the teachings of Malm demonstrate that transplantation of allogenic islet in mice induces an inflammatory state which can be mitigated by blocking the CD28-B7 and the CD40-CD40L pathways, and thus in practicing the obvious method of reference claims 34 and 37-39 modified as described above the ordinarily skilled artisan will necessarily be practicing the method of the instant claims, including instant claim 140. Note further that the “CD40L-specific monomer” of reference claim 38 and the “Tn3 scaffold” of reference claim 39 each comprise particular AB, BC, CD, DE, EF and FG loops recited, e.g., in instant claim 124. Finally, note that “the Tn3 scaffold [comprising] at least one CD40L-specific monomer subunit” of the reference claims will inherently “reduc[e] binding of CD40 ligand (CD40L) to the CD40 receptor” as recited in instant claim 127 and dependent claims thereof since this property is inherent to the structure of the Tn3 scaffold of the reference claims.
Claims 122-127, 134 and 135 and rejected on the ground of nonstatutory double patenting as being unpatentable over claims 34 and 37-39 of U.S. Patent No. 11555062 in view of Seung et al. (Blood. 2000;95:2175-2182, cited herewith).
Reference claim 34 recites,
“[a] method, comprising administering an effective amount of a composition comprising a Tn3 scaffold to a subject with a disorder comprising inflammation, wherein the Tn3 scaffold comprises at least one CD40L-specific monomer subunit, wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 4, the BC loop comprises a sequence selected from the group consisting of SEQ ID NOS: 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 168, the CD loop comprises SEQ ID NO: 6, the DE loop comprises a sequence selected from the group consisting of SEQ ID NOs: 94, 95, 96, 97, 98, and 169, the EF loop comprises SEQ ID NO: 8, and the FG loop comprises a sequence selected from the group consisting of SEQ ID NOS: 9, 99, 139, and 170.”
(emphasis added)
Dependent reference claims 37-39 further specify,
“[t]he method of claim 34, wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, wherein the A beta strand consists of SEQ ID NO:11, the B beta strand consists of SEQ ID NO:12, the C beta strand consists of SEQ ID NO:13 or SEQ ID NO:14, the D beta strand consists of SEQ ID NO:15, the E beta strand consists of SEQ ID NO:16, the F beta strand consists of SEQ ID NO:17, and the G beta strand consists of SEQ ID NO:18, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop consists of SEQ ID NO: 4, the BC loop consists of SEQ ID NO: 86, the CD loop consists of SEQ ID NO: 6, the DE loop consists of SEQ ID NO: 96, the EF loop consists of SEQ ID NO: 8, and the FG loop consists of SEQ ID NO: 139,” and“[t]he method of claim 34, wherein the CD40L-specific monomer subunit comprises SEQ ID NO: 146,” and
“[t]he method of claim 34, wherein the Tn3 scaffold comprises SEQ ID NO: 145,”
respectively.
However, the reference claims do not explicitly recite “A method of reducing binding of CD40 ligand (CD40L) to CD40 receptor comprising administering an effective amount of a composition comprising a Tn3 scaffold to a subject in need, wherein the Tn3 scaffold comprises at least one CD40L- specific monomer subunit, wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 4, the BC loop comprises a sequence selected from the group consisting of SEQ ID NOS: 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 168, the CD loop comprises SEQ ID NO: 6, the DE loop comprises a sequence selected from the group consisting of SEQ ID NOs: 94, 95, 96, 97, 98, and 169,the EF loop comprises SEQ ID NO: 8, and the FG loop comprises a sequence selected from the group consisting of SEQ ID NOS: 9, 99, 139, and 170, ” wherein the method is effective in reducing graft-vs-host disease in the subject.
Seung teaches the use of an anti-CD154 antibody capable of blocking the CD40L-CD40 interaction to “establish robust allogeneic hematopoietic chimerism in sublethally irradiated mice without subsequent GVHD by blocking the CD40-CD154 costimulatory pathway using as few as 2 injections of anti-CD154 antibody.” (see Abstract). As further described at page 2180, right col., 4th full paragraph, “The second major effect of costimulatory blockade was on the occurrence of GVHD. Treatment with anti-CD154 mAb was clearly associated with prevention of GVHD in successful chimeras. With few exceptions, chimeras generated using irradiation
alone showed clinical characteristics of GVHD. In contrast, chimeras generated with the same dose of radiation but with the addition of anti-CD154 mAb showed no evidence of this common
complication, either acutely or chronically, for up to about 11 months after bone marrow transplantation. These observations are consistent with previous reports documenting that treatment with anti-CD154 mAb can prevent GVHD in a model system based on the transfer of alloreactive T cells.9-11 These earlier studies demonstrated that anti-CD154 mAb can block the graft-versus-host activity of transferred alloreactive CD8+ T cells.”
Considering the reference claims in the context of the teaching of Seung, it would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to reduce the inflammatory reaction which is graft-versus-host disease, e.g., as occurs when allogeneic hematopoietic stem cells are transplanted into a recipient, by making use of the method of the reference claims.
One reason the one of ordinary skill in the art would have been motivated to practice the method of reference claim 34 in the context of allogeneic hematopoietic stem cell transplantation was because, unlike conventional anti-CD40L antibodies, the Tn3 scaffold of the reference claims would not be expected by the skilled artisan to trigger Fc-mediated complications well known in the prior as described in the instant specification at paragraph 14.
Note that, as described above, the teachings of Seung demonstrate that an anti-CD154 antibody was capable of blocking the CD40L-CD40 interaction to “establish robust allogeneic hematopoietic chimerism in sublethally irradiated mice without subsequent GVHD by blocking the CD40-CD154 costimulatory pathway, and thus in practicing the obvious method of reference claims 34 and 37-39 modified as described above to ameliorate GVHD in the context of allogeneic hematopoietic stem cell transplantation the ordinarily skilled artisan will necessarily be practicing the method of instant claim 127, and dependent claims thereof. Note further that the “CD40L-specific monomer” of reference claim 38 and the “Tn3 scaffold” of reference claim 39 each comprise particular AB, BC, CD, DE, EF and FG loops recited, e.g., in instant claim 124. Finally, note that “the Tn3 scaffold [comprising] at least one CD40L-specific monomer subunit” of the reference claims will inherently “reduc[e] binding of CD40 ligand (CD40L) to the CD40 receptor” as recited in instant claim 127 and dependent claims thereof since this property is inherent to the structure of the Tn3 scaffold of the reference claims.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 122-130, 132-134, 136, 138, 141 and 142 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over various claims of the various reference applications as outlined below. Although the claims at issue are not identical, they are not patentably distinct from each other because, for the reasons set forth below the reference claims anticipate the instant claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The following co-pending patent applications are each drawn to methods of treating various species of autoimmune diseases encompassed in the breadth of the instant claims by administering a CD40L-binding Tn3 scaffold having a structure that is the same as the CD40L-binding Tn3 scaffold of the instant claims: 18612452, 18612472, 18615679 and 18509836 (see charts below).
Thus, claims 122-130, 132-134, 136, 138, 141 and 142 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the reference claims and reference U.S. Application Nos. as set forth in the charts below.
Reference U.S. Application No.
Reference claims
Anticipate instant claims
18615679
1, 3-6, 10, 12, 13, 15-18, 21, 22, 30-35
122-128, 130, 132
18612472
122-146
122-130 and 132-134
18612452
1-8, 10, 14-17, 22-26, 29, 32, 33, 36, 37
122-129
18509836
34-38, 41-43, 45-55, 60-62
122-128, 133, 136, 138, 141 and 142.
CD
Instant claims:
Loops
SEQ ID NO:
SEQUENCE
AB
4
KDVTDTT
BC
86
SDDFGEYVW
CD
6
KDVPGDR
DE
96
WYHHAH
EF
8
GNLKPDTE
FG
139
RSGDMSSNPA
Strands
A
11
“000” (“IEV”?)
B
12
ALITW
C
13 or 14
CELAYGI or CELTYGI
D
15
TTIDL
E
16
“000” (“YSI”?)
F
17
YEVSLIC
G
18
KETFTT
18612452
Loops
SEQ ID NO:
SEQUENCE
AB
11
KDVTDTT
BC
12
SDDFGEYVW
CD
13
KDVPGDR
DE
14
WYHHAH
EF
15
GNLKPDTE
FG
16
RSGDMSSNPA
Strands
A
5
“000” (“IEV”?)
B
6
ALITW
C
17
CELTYGI
D
18
TTIDL
E
19
“000” (“YSI”?)
F
20
YEVSLIC
G
21
KETFTT
18612472
SEQ ID NO:
SEQUENCE
1
Comprises two monomers, each monomer is SEQ ID NO: 3
3
See above, N.B. – the monomer displayed to the right comprises each of the loops and strands explicitly recited in the tables above
IEVKDVTDTTALITWSDD
FGEYVWCELTYGIKDVPG
DRTTIDLWYHHAHYSIGNL
KPDTEYEVSLICRSGDMSSN
PAKETFTT
18615679
Loops
SEQ ID NO:
SEQUENCE
AB
11
KDVTDTT
BC
12
SDDFGEYVW
CD
13
KDVPGDR
DE
14
WYHHAH
EF
15
GNLKPDTE
FG
16
RSGDMSSNPA
Strands
A
5
“000” (“IEV”?)
B
6
ALITW
C
17
CELTYGI
D
18
TTIDL
E
19
“000” (“YSI”?)
F
20
YEVSLIC
G
21
KETFTT
18509836
Loops
SEQ ID NO:
SEQUENCE
AB
11
KDVTDTT
BC
12
SDDFGEYVW
CD
13
KDVPGDR
DE
14
WYHHAH
EF
15
GNLKPDTE
FG
16
RSGDMSSNPA
Strands
A
5,23,24
“000” (“IEV”?), RLDAPSQIEV, SQIEV
B
6
ALITW
C
17
CELTYGI
D
18
TTIDL
E
19
“000” (“YSI”?)
F
20
YEVSLIC
G
21
KETFTT
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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