DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1, 4, 8, 21-22, and 24-26 have been cancelled.
Specification
The substitute specification filed 2/3/2023 has been entered.
Drawings
The replacement drawings for Figures 1A-1C, 2A-2C, 3A-3E, 4A-4C, 6A-6C, 7A-7B, 8A-8C, 10A-10C, and 11A-11B were received on 2/3/2023. These drawings are acceptable.
Claim Objections
Claim 5 is objected to because of the following informalities: Claim 5 includes an extraneous period (“.”) in the middle of the claim at “respectively;. (11) SEQ ID NOs: 170…”. Appropriate correction is required.
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 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 2, 12-15, 17, 19-20, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 41-42, 47-48, 52, and 57 of copending Application No. 18/281,849 (common inventors, common applicant, 9/13/2023 claim set). Although the claims at issue are not identical, they are not patentably distinct from each other.
Co-pending claim 1 is directed to an antibody fusion protein comprising an Ang2 antibody. Co-pending claim 9 depends upon co-pending claim 1. The Ang2 antibodies of co-pending claim 9, parts (1)-(5), correspond to those of instant claim 2, parts (9), (7), (8), (10), and (20), respectively. Co-pending claim 9 puts the antibodies of instant claim 2 in the hands of one of ordinary skill in the art. These antibodies bind human Ang2. See instant claim 12. The fusion proteins of the co-pending claims meet the limitations of instant claim 13. Co-pending claims 41-42 meet the limitations of instant claims 14-15. Co-pending claim 47 meets the limitation of instant claim 17. Co-pending claims 48, 42, and 57 meet the limitations of instant claims 19-20 and 23.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. The co-pending application is junior to the instant application.
Claims 2, 7, 9-11, and 14-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 41-42, 47-48, 52, and 57 of copending Application No. 18/281,849 (common inventors, common applicant, 9/13/2023 claim set) in view of Brinkmann et al. (U.S. Patent No. 9,340,609).
The copending claims are as set forth above. The copending claims do not recite the structural features of instant claims 7, 9-11, and 16.
Brinkmann et al. (U.S. Patent No. 9,340,609) discloses that Ang2 antibodies can be of the IgG1 and IgG4 subclass. (See at least column 9, lines 13-14). The antibodies can include a kappa chain and IgG4 subclasses that show reduced Fc receptor binding. (See at least column 13, lines 17-47). See instant claims 7, 9, and 10. The antibodies can be monoclonal, chimeric, and humanized. (See at least column 9, line 46, through column 10, line 19). See instant claim 11. Antibodies can be produced recombinantly using nucleic acids, vectors, and host cells. (See at least column 14, lines 45-67.) See instant claims 14-16.
It would have been obvious to produce the Ang2 antibodies of the copending claims recombinantly in host cells (instant claim 16) using the nucleic acids and expression vectors of the co-pending claims. It would have been obvious to have them be humanized or chimeric (instant claim 11) and have an IgG4 format with reduced Fc receptor binding (instant claims 7 and 9) and a kappa light chain (instant claims 7 and 10) as taught by Brinkmann et al. One would have been motivated to do so antibodies with these features would have been routine and conventional to those of ordinary skill in the art.
This is a provisional nonstatutory double patenting rejection.
Claims 2 and 17-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 41-42, 47-48, 52, and 57 of copending Application No. 18/281,849 (common inventors, common applicant, 9/13/2023 claim set) in view of Green et al. (U.S. Patent No. 8,834,880).
The copending claims are as set forth above. Co-pending claim 47 meets the limitation of instant claim 17. The copending claims do not recite the limitations of claim 18.
Green et al. (U.S. Patent No. 8,834,880) discloses administering anti-Ang2 antibodies with additional anti-tumor agents to treat cancer. See at least column 8, lines 26-54.
It would have been obvious to combine the antibodies of the copending claims with additional therapeutic agents such as anti-tumor agents as taught by Green et al. thereby arriving at the composition of instant claim 18. One would have been motivated to do so in order to provide new therapeutic compositions.
This is a provisional nonstatutory double patenting rejection.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 12, 19-20, 23, and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for antibodies and methods as discussed below, does not reasonably provide enablement for all methods embraced by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Claim 19 is directed to a method for treating an Ang2-related disease in a subject in need thereof, comprising administering the subject a therapeutically effective amount of the composition of claim 17. Claim 20 specifies that the disease is cancer, an inflammatory disease or an infectious disease. Claim 23 indicates that the inflammatory disease is sepsis, macular edema, diabetic retinopathy or age-related macular degeneration. Claim 27 is directed to methods for stabilizing the vasculature or reducing vascular inflammation in a subject in need thereof.
Example 1 discloses immunizing mice and rats with human Ang2 proteins and selecting 52 hybridomas.
Example 2 characterized the anti-Ang2 mouse antibodies in vitro. As shown in FIGS.1A-1C, the antibodies 4D8F2, 5A7B9, 42A2A6, 42C3A4, 46F3H4, 46H3H3 and 49E4C2 bound to human Ang2 proteins (FIG. 1A), but showed undetectable binding activity to mouse Ang2 (FIG. 1B); some other anti- Ang2 antibodies of the disclosure showed binding activities to human Ang2 (FIG. 1C). As shown in FIGS. 2A-2C, seven antibodies bound to human (FIG. 2A) and cyno (FIG. 2B) Ang2 proteins. Two antibodies (49E4C2 and 42C3A4) bound to mouse Ang2 proteins (FIG. 2C) in FACS. Phos-AKT bioassay results are shown in FIGS. 3A-3E. Compared with ABTAA, several antibodies of the disclosure functioned as better Tie2 agonists, including 4D8F2, 5A7B9, 5F7D7 and 46F3H4 (FIG. 3A), 50H8G3 (FIG. 3B), 17F3E8, 7F10B2 and 31E2D4 (FIG. 3C), 50H8ESC5, 25C5D6F3 and 15H10D12 (FIG. 3D), and 82B10C1 (FIG. 3E). As shown in FIGS. 4A-4C, antibodies 45CS5A1 (FIG. 4A), 53E8B2, 60C4B9, 73H11G10, 85E10B9 (FIG. 4B), 55D3F10 and 98C7H11 (FIG. 4C) were capable of blocking Ang2 binding to Tie2.
Example 3 discloses producing chimeric antibodies.
Example 4 discloses producing humanized antibodies. See Tables 2-3.
None of the examples administer any of the antibodies to subjects for treatment as in claims 19-20 and 23 or to stabilize vasculature or reduce vascular inflammation as in claim 27. Note that not all of the antibodies encompassed by claim 2 were tested for or had the properties recited in claim 12. See in particular inhibiting Ang2 binding to integrins. Note that claim 12 includes embodiments of antibodies having all of the recited properties (“and/or”). It is not known from the specification which antibodies of claim 2 possess which properties (i.e. some or all of the recited properties).
While antibodies against angiopoietin-2 (Ang2) have been shown to inhibit tumor growth (see for example claims of Brinkmann et al., U.S. Patent No. 9,340,609) and to inhibit angiopoietin-2 induced angiogenesis (see for example claims of Green et al., U.S. Patent No. 8,834,880 and claims of Boone et al., U.S. Patent No. 8,221,749), these art recognized methods do not enable the scope of the method claims.
Page 21 of the specification defines “therapeutically effective amount” as an amount of the antibody or antigen-binding portions thereof of the present disclosure sufficient to prevent or reduce the symptoms associated with a disease or condition (such as cancer or sepsis) and/or lessen the severity of the disease or condition.
Page 21 of the specification defines “treat” or “treating” as an action that suppresses, eliminates, reduces, and/or ameliorates a symptom, the severity of the symptom, and/or the frequency of the symptom associated with the disease or disorder being treated.
As such, “treatment” as recited in the claims is considered to include prevention and cure. At least for example, there are no known cures or methods for preventing age-related macular degeneration or sepsis. With respect to ameliorating symptoms of the disease, there is no evidence or reason to believe that vision loss due to diabetic retinopathy, macular edema, or age-related macular degeneration will be reversed or restored by administration of the claimed antibodies. At least for example, there is no evidence or reason to believe that severe organ failure or tissue damage caused by sepsis will be reversed or restored by administration of the claimed antibodies. There is no evidence of record nor reason to believe that tissue destruction due to cancer will be reversed or restored by administration of the claimed antibodies. Again, claims 19-20 and 23 require no particular therapeutic effect and as such, must enable all therapeutic effects encompassed by the claims. The scope of the methods of treatment claims are not enabled.
It would constitute undue experimentation to determine which, if any, antibodies of claim 2 could be used in the methods of claims 19-20, 23, and 27 given the large number of antibodies, their structural variability, and the lack of information regarding their properties; the large number of disorders and therapeutic effects encompassed by the claims; and the lack of direction, guidance, and examples in the specification. The scope of the claims is not enabled.
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.
Claims 3, 6, 19-20, 23, and 27 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 is directed to the isolated monoclonal antibody, or the antigen-binding portion thereof, of claim 2, wherein the heavy chain variable region comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to any one of SEQ ID NOs: 160 to 209, 255, 325, 260 to 296 and 326 to 335; and wherein the light chain variable region comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to any one of SEQ ID NOs: 210 to 247, 256, 297 to 324 and 336 to 345. Based on its dependency upon claim 2, an antibody of claim 3 must retain the six CDRs recited for one of the antibodies listed as (1)-(50) in claim 2 in order to be properly dependent. The language of claim 3 does not make this clear as any heavy chain variable region can be selected and any light chain variable region can be selected (in addition to the percent identity limitations). At least for example, this would include combinations such as the VH of SEQ ID NO: 160 and the VL of SEQ ID NO: 345. None of antibodies (1)-(50) in claim 2 have the three VH CDRs in SEQ ID NO: 160 and the three VL CDRs in SEQ ID NO: 345. The claim is confusing and does not appear to be properly dependent.
Claim 6 depends upon claim 2 and recites heavy chain variable region and light chain variable region pairs. Based on its dependency upon claim 2, an antibody of claim 3 must retain the six CDRs recited for one of the antibodies listed as (1)-(50) in claim 2. However, at least claim 6, parts (18), (19), and (20), do not contain the VH CDRs for the 4D8F2 antibody in claim 2, part (5). See at least Tables 1 and 2. The claim is confusing and does not appear to be properly dependent. Given the number of sequences recited in the claims, applicant is requested to verify that all sequences recited in claim 6 contain CDRs as recited in claim 2. The examiner has made a good faith effort to verify this but has not done an exhaustive check for all CDRs.
Claim 19 recites an “Ang2-related disease.” The term “related” in claim 19 is a relative term which renders the claim indefinite. The term “related” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As claim 20 depends upon claim 19, claim 20 is unclear as to which cancers, inflammatory diseases or infectious diseases are intended. For example, claim 23 is interpreted as meaning sepsis related to Ang2 and not sepsis due to other causes. If this is not what was intended, then the claim is unclear. In addition, claim 19 is confusing as it requires administering a “therapeutically effective amount” with specifying what therapeutic result must occur. Note that none of claims 19, 20, or 23 require any particular therapeutic effect with respect to Ang2 or the recited disease.
Claim 27 is directed to a method for stabilizing the vasculature or reducing vascular inflammation in a subject in need thereof. Those subjects with vascular inflammation would be in need of reducing vascular inflammation, but the specification does not make clear what subjects would be in need of stabilizing their vasculature. As the claim is written, these subjects have no particular disease or condition or vascular instability. There does not appear to be a definition of vascular stability or instability. The metes and bounds of the population to be treated cannot be determined.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 17 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 17 requires nothing more than the antibody or antigen binding portion thereof of claim 2. It does not further limit claim 2. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claims 2-3, 5-7, 9-20, 23, and 27 are free of the prior art. The prior art does not disclose monoclonal antibodies, or antigen-binding portions thereof, that specifically bind to angiopoietin 2 having the sequences recited in the instant claims.
The VH and VL CDRs recited in claim 2, parts (1)-(50), correspond to the antibodies numbered 10, 2-9, 1, 11-41, and 44-52, respectively, in Table 1 on pages 25-26 of the specification. Note that the antibodies numbered 33, 42, and 43 in Table 1 have the same CDRs.
Claim 5 depends upon claim 2. The antibodies having the VH/VL pairs recited in claim 5 must retain the six CDRs recited for one of the antibodies listed as (1)-(50) in claim 2 in order to be properly dependent. Claim 5, parts (1) through (32) and (34) through (52), correspond to claim 2, parts (10), (2) through (9), (1), (11) through (32), and (34) through (52), respectively. Claim 5, parts (33), (42), and (43), all have the CDRs of claim 2, part (33).
Claim 6 depends upon claim 2. The antibodies having the VH/VL pairs recited in claim 5 must retain the six CDRs recited for one of the antibodies listed as (1)-(50) in claim 2 in order to be properly dependent. Claim 6, parts (1) through (9), appear to have the CDRS of claim 2, part (29) for antibody 46H3H3. Claim 6, parts (10) through (16), appear to have the CDRs of claim 2, part (2), for antibody 42C3A4. Claim 6, parts (17), (21), and (22), appear to have the CDRs of claim 2, part (5), for antibody 4D8F2. (See above for errors in claim 6, parts (18) through (20).) Claim 6, part (23), appears to have the CDRs of claim 2, part (31), for antibody 49E4C2. Claim 6, parts (24) through (31), appear to have the CDRs of claim 2, part (19), for antibody 42A2A6. Claim 6, parts (32) through (50), appear to have the CDRs of claim 2, part (7) for antibody 5A7B9. Claim 6, parts (51) through (54), appear to have the CDRs of claim 2, part (13) for antibody 17F3E8. Claim 6, parts (55) through (60), appear to have the CDRs of claim 2, part (1) for antibody 31E2D4. Claim 6, parts (61) through (63), appear to have the CDRs of claim 2, part (8) for antibody 5F7D7. Claim 6, parts (64) through (72), appear to have the CDRs of claim 2, part (9) for antibody 7F10B2. Claim 6, parts (73) through (76) and (80), appear to have the CDRs of claim 2, part (43), for antibody 53E8B2. Claim 6, parts (77) through (79) appear to have the CDRs of claim 2, part (50) for antibody 85E10B9. Claim 6, part (81), appears to have the CDRs of claim 2, part (44), for antibody 60C4B9. Claim 6, part (82), appears to have the CDRs of claim 2, part (45), for antibody 73H11G10. Claim 6, part (83), appears to have the CDRs of claim 2, part (48), for antibody 98C7H11. Claim 6, parts (84) through (86) appear to have the CDRs of claim 2, part (47), for antibody 55D3F10. See Tables 1-3.
The art made of record and not relied upon is considered pertinent to applicant's disclosure.
WO 2022/199603 discloses antibodies related to the instant application. It is not prior art against the instant application. U.S. Patent Application 18/281,849 is a 371 application of WO 2022/199603. The PGPUB for U.S. Patent Application 18/281,849 is U.S. Patent Application Publication 2024/0182553. It is not prior art against the instant application.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE P ALLEN whose telephone number is (571)272-0712. The examiner can normally be reached 7:00-3:30 EST Monday-Friday.
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/Marianne P Allen/Primary Examiner, Art Unit 1647
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