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 .
Election/Restrictions
Claims 13-19, 21-24, and 27-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II and III, there being no allowable generic or linking claim. Election of Group I was made without traverse in the reply filed on June 4, 2026.
Claim Rejections - 35 USC § 112
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 7 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. BRI of claim 7 includes a fusion protein comprising short fragments of SEQ ID NOs: 2, 4, 6, and 8 with less than 95% identity because of the indefinite article prior to “amino acid sequence”. Claim 2, from which claim 7 depends, excludes these fragments of SEQ ID NOs: 2, 4, 6, and 8. Therefore, claim 7 fails to include all of the limitations of the claim upon which it depends. 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.
This rejection could be overcome by amending claim 7 to state “the amino acid sequence of SEQ ID NO: 2”, “the amino acid sequence of SEQ ID NO: 4”, “the amino acid sequence of SEQ ID NO: 6” and “the amino acid sequence of SEQ ID NO: 8”.
Claims 10-11 are 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. BRI of claim 10 includes a fusion protein comprising short fragments of SEQ ID NO: 12 because of the indefinite article prior to “amino acid sequence”. Claim 8, from which claim 10 depends, excludes these fragments of SEQ ID NO: 12 because of the definite article prior to “amino acid sequence”. Therefore, claim 10 fails to include all of the limitations of the claim upon which it depends. 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.
Claim 11 fails to remedy this issue and is likewise rejected.
This rejection could be overcome by amending claim 10 to state “the amino acid sequence of SEQ ID NO: 12”.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 4, 5, and 7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hu (CN103304668-A, published 18-Sept-2013; English translation generated in PE2E SEARCH).
Hu teaches a recombinant fusion protein SEQ ID NO: 1 comprising ([0017], Figure 1, sequence listing):
- an Ig-like domain of a first VEGF receptor that is 100% identical to Ig-like domain 2 of human VEGFR-1 (flt-1) and 100% identical to instant SEQ ID NO: 2 (yellow highlight),
- an Ig-like domain of a second VEGF receptor that is 100% identical to Ig-like domain 3 of human VEGFR-2 (KDR) and 100% identical to instant SEQ ID NO: 4 (green highlight),
- at least an Ig-like domain of a third VEGF receptor that is 100% identical to Ig-like domains 1, 2, and 3 of human VEGFR-3 and 100% identical to instant SEQ ID NO: 15 (blue highlight, comprises instant SEQ ID NO: 6, the amino acid sequence corresponding to positions 104-106 of instant SEQ ID NO: 13 is NDT), and
- a multimerization component comprising an Fc domain of human IgG1 100% identical to instant SEQ ID NO: 8 (grey highlight).
Qy 1 SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 21 SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS 80
Qy 61 RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 81 RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL 140
Qy 121 VLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 141 VLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQ 200
Qy 181 GLYTCAASSGLMTKKNSTFVRVHEK----------------------------------- 205
|||||||||||||||||||||||||
Db 201 GLYTCAASSGLMTKKNSTFVRVHEKGPGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM 260
Qy 206 ------------------------------------------------------------ 205
Db 261 ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 320
Qy 206 ------------------------------------------------------------ 205
Db 321 WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDKLTKNQVSLTCLVKGF 380
Qy 206 ------------------------------------------------------------ 205
Db 381 YPSDIAVEWESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL 440
Qy 206 ------------------------------------YSMTPPTLNITEESHVIDTGDSLS 229
||||||||||||||||||||||||
Db 441 HNHYTQKSLSLSPGKZMETDTLLLWVLLLWVPGSTGYSMTPPTLNITEESHVIDTGDSLS 500
Qy 230 ISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGS 289
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 501 ISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGS 560
Qy 290 YVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVT 349
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 561 YVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVT 620
Qy 350 LRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNE 409
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 621 LRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNE 680
Qy 410 LYDIQLLPRKSLELLVGEKLVLNCTVWAEFNSGVTFDWDYPGKQAERGKWVPERRSQQTH 469
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 681 LYDIQLLPRKSLELLVGEKLVLNCTVWAEFNSGVTFDWDYPGKQAERGKWVPERRSQQTH 740
Qy 470 TELSSILTIHNVSQHDLGSYVCKANNGIQRFRESTEVIVHEN---DKTHTCPPCPAPELL 526
|||||||||||||||||||||||||||||||||||||||||| |||||||||||||||
Db 741 TELSSILTIHNVSQHDLGSYVCKANNGIQRFRESTEVIVHENPFIDKTHTCPPCPAPELL 800
Qy 527 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 586
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 801 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 860
Qy 587 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR 646
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 861 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR 920
Qy 647 DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 706
|||||||||||||||||||||||||||||||||||| |||||||||||||||| ||||||
Db 921 DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKS 980
Qy 707 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 737
|||||||||||||||||||||||||||||||
Db 981 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 1011
SEQ ID NO: 1 of CN103304668-A satisfies all of the limitations of instant claims 1, 2, 4, 5, and 7.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hong (WO 2018/111196 A1, published 21 June 2018).
Hong teaches a recombinant fusion protein comprising:
(C0-1-A1-2-B0-1-C2-3-D)2-5
wherein
each A is an Ig-like domain independently selected from domain 1 (D1) and domain 2 (D2) of a first VEGFR, VEGFR-1;
B is an Ig-like domain 3 (D3) of a second VEGFR, VEGFR-2;
each C is an Ig-like domain selected from domain 1 (D1), domain 2 (D2), and domain 3 (D3) of a third VEGFR, VEGFR-3;
D is a multimerization component ([0006]).
The polypeptide is selected from the group consisting of ([0012]):
(D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - Fc of human IgG)2;
(D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - Human Ficolin2)3;
(D1 of VEGFR1 - D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - Fc of human IgG)2;
(D1 of VEGFR1 - D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - Human Ficolin2)3;
(D1 of VEGFR1 - D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - MBPC101-248)3;
(D1 of VEGFR1 - D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - MBPC101-248)3;
(D1 of VEGFR1 - D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - COMP)5;
(D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - MBPC101-248)3;
(D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - MBPC101-248)3;
(D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - COMP)5;
(D1 of VEGFR3 - D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - Fc of human IgG)2;
(D1 of VEGFR3 - D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - Human Ficolin2)3;
(D1 of VEGFR3 - D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - MBPC101-248)3;
(D1 of VEGFR3 - D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - MBPC101-248)3;
(D1 of VEGFR3 - D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - COMP)5;
(D1 of VEGFR1 - D2 of VEGFR1 - D2 of VEGFR3 - D3 of VEGFR3 - MBPC101-248)3;
wherein the VEGFR3 sequence disclosed by Hong is identical to instant SEQ ID NO: 13 and comprises NDT at positions 104-106 ([0069]).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This 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.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Hu (CN103304668-A, published 18-Sept-2013; English translation generated in PE2E SEARCH).
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Determining the scope and contents of the prior art.
Hu teaches a fusion protein SEQ ID NO: 1 comprising ([0017], Figure 1, sequence listing):
- an Ig-like domain of a first VEGF receptor that is 100% identical to Ig-like domain 2 of human VEGFR-1 (flt-1) and 100% identical to instant SEQ ID NO: 2 (yellow highlight),
- an Ig-like domain of a second VEGF receptor that is 100% identical to Ig-like domain 3 of human VEGFR-2 (KDR) and 100% identical to instant SEQ ID NO: 4 (green highlight),
- at least an Ig-like domain of a third VEGF receptor that is 100% identical to Ig-like domains 1, 2, and 3 of human VEGFR-3 and 100% identical to instant SEQ ID NO: 15 (blue highlight, comprises instant SEQ ID NO: 6, the amino acid sequence corresponding to positions 104-106 of instant SEQ ID NO: 13 is NDT), and
- a multimerization component comprising an Fc domain of human IgG1 100% identical to instant SEQ ID NO: 8 (grey highlight). See alignment above for the overlap with the VEGFR Ig-like domains.
Ascertaining the differences between the prior art and the claims at issue.
Hu does not teach a fusion protein comprising an amino acid sequence that is at least 95% identical to instant SEQ ID NO: 12. The alignment between SEQ ID NO: 1 of Hu (Db) and instant SEQ ID NO: 12 (Qy) is as follows:
The following is an alignment between instant SEQ ID NO: 12.
Qy 1 SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 21 SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDS 80
Qy 61 RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 81 RKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKL 140
Qy 121 VLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 141 VLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQ 200
Qy 181 GLYTCAASSGLMTKKNSTFVRVHEK----------------------------------- 205
|||||||||||||||||||||||||
Db 201 GLYTCAASSGLMTKKNSTFVRVHEKGPGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM 260
Qy 206 ------------------------------------------------------------ 205
Db 261 ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD 320
Qy 206 ------------------------------------------------------------ 205
Db 321 WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDKLTKNQVSLTCLVKGF 380
Qy 206 ------------------------------------------------------------ 205
Db 381 YPSDIAVEWESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL 440
Qy 206 ------------------------------------YSMTPPTLNITEESHVIDTGDSLS 229
||||||||||||||||||||||||
Db 441 HNHYTQKSLSLSPGKZMETDTLLLWVLLLWVPGSTGYSMTPPTLNITEESHVIDTGDSLS 500
Qy 230 ISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGS 289
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 501 ISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGS 560
Qy 290 YVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVT 349
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 561 YVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVT 620
Qy 350 LRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNE 409
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 621 LRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNE 680
Qy 410 L----------------------------GGSG--------GGSGGGGS----------- 422
| || | |
Db 681 LYDIQLLPRKSLELLVGEKLVLNCTVWAEFNSGVTFDWDYPGKQAERGKWVPERRSQQTH 740
Qy 423 -----------------GGGGGSGGGG------------------DKTHTCPPCPAPELL 447
| | |||||||||||||||
Db 741 TELSSILTIHNVSQHDLGSYVCKANNGIQRFRESTEVIVHENPFIDKTHTCPPCPAPELL 800
Qy 448 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 507
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 801 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 860
Qy 508 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR 567
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 861 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR 920
Qy 568 DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 627
|||||||||||||||||||||||||||||||||||| |||||||||||||||| ||||||
Db 921 DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKS 980
Qy 628 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 658
|||||||||||||||||||||||||||||||
Db 981 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 1011
Resolving the level of ordinary skill in the pertinent art.
Hu teaches that the fusion protein is an Ultra-VEGF-trap immune fusion protein capable of simultaneously binding VEGF-A, -B, -C, and -D ([0007], [0017]). Hu teaches that in addition to SEQ ID NO: 1, the invention includes amino acid sequences of SEQ ID NO: 1 wherein one or several amino acids or a segment derived from a protein is deleted from SEQ ID NO: 1 ([0008]). Hu demonstrates that recombinant production of these proteins is within the skill of the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The specification does not include a comparison between instant SEQ ID NO: 1 and the closest prior art SEQ ID NO: 1 of Hu.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to delete the segment of SEQ ID NO: 1 of Hu between the Ig-like domain of VEGFR-2 and VEGFR-3 to yield a fusion protein with at least 95% identity to instant SEQ ID NO: 12. The rationale for obviousness is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention (MPEP § 2143.01(G)). The relevant findings for this rationale are as follows.
(1) There was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings. In the instant case, Hu teaches that the Ultra-VEGF-trap immune fusion protein SEQ ID NO: 1 can be modified by deletion of a segment derived from a protein ([0008]). One of ordinary skill in the art would have been motivated to delete a segment of SEQ ID NO: 1 based on this explicit teaching in Hu. One of ordinary skill in the art would be motivated to choose a segment that would not disrupt binding to VEGF-A, -B, -C, and -D because Hu teaches that this is the desired function of the fusion protein ([0017]). Therefore, one of ordinary skill in the art would specifically chose to delete the segment of SEQ ID NO: 1 located between the Ig-like domain of VEGFR-2 and the Ig-like domain of VEGFR-3 because the Ig-like domains are responsible for VEGF-A, -B, -C, and -D binding and need to be preserved. Therefore, there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings.
(2) There was reasonable expectation of success. One of ordinary skill in the art would predict that deleting the segment of SEQ ID NO: 1 located between the Ig-like domain of VEGFR-2 and the Ig-like domain of VEGFR-3 would result in a fusion protein that is still capable of binding VEGF-A, -B, -C, and -D because Hu teaches that the Ig-like domains of the VEGFRs are responsible for this function. Therefore, there was a reasonable expectation of success.
(3) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. The specification does not provide a comparison between the claimed sequence and the closest prior art. Therefore, there is no evidence of unexpected results on record.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006). Therefore, claim 8 is obvious over the cited art.
Claims 1-2, 4-5, and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Hong (WO 2018/111196 A1, published 21 June 2018).
Determining the scope and contents of the prior art
Hong teaches a recombinant fusion protein comprising:
(C0-1-A1-2-B0-1-C2-3-D)2-5
wherein
each A is an Ig-like domain independently selected from domain 1 (D1) and domain 2 (D2) of a first VEGFR, VEGFR-1;
B is an Ig-like domain 3 (D3) of a second VEGFR, VEGFR-2;
each C is an Ig-like domain selected from domain 1 (D1), domain 2 (D2), and domain 3 (D3) of a third VEGFR, VEGFR-3;
D is a multimerization component ([0006]).
wherein the VEGFR3 sequence disclosed by Hong is identical to instant SEQ ID NO: 13 and comprises NDT at positions 104-106 ([0069]) and
wherein
D2 of VEGFR1 is at least 90% identical to SEQ ID NO: 2 (same as instant SEQ ID NO: 2),
D3 of VEGFR2 is at least 90% identical to SEQ ID NO: 3 (same as instant SEQ ID NO: 4),
D1 of VEGFR3 is at least 90% identical to SEQ ID NO: 6,
D2 of VEGFR3 is at least 90% identical to SEQ ID NO: 4,
D3 of VEGFR3 is at least 90% identical to SEQ ID NO: 5 (D1-D2 is same as instant SEQ ID NO: 6 and D1-D2-D3 is same as instant SEQ ID NO: 15),
D is Fc of human IgG SEQ ID NO: 7 (same as instant SEQ ID NO: 8) (see claims 5-9).
Ascertaining the differences between the prior art and the claims at issue
The genus of Hong includes Fc fusion proteins comprising
D2 of VEGFR1 - D3 of VEGFR2 - D1 of VEGFR3 - D2 of VEGFR3 - D3 of VEGFR3 - Fc of human IgG (e.g. a protein with at least 95% identity to SEQ ID NO: 12) but does not reduce to practice or explicitly disclose this embodiment.
Hong reduces to practice numerous embodiments comprising ([0012])
D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - D
The closest embodiment to the subgenera instant claims 2, 4-5, and 7 and to instant SEQ ID NO: 12 disclosed by Hong is ([0012]):
(D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - Fc of human IgG)2.
Therefore, the closest embodiment in Hong is missing D1 of VEGFR3.
Resolving the level of ordinary skill in the pertinent art.
Hong discloses methods for the recombinant expression and purification of the fusion polypeptides (Examples 1 and 2) as well as functional assays (Examples 3-8).
Hong establishes that it is known in the art that VEGF overexpression contributes to development of various angiogenesis-related disorders, vascularization-related disorders, proliferative disorders, and eye disorders ([0052]).
Hong establishes that it is known in the art that the VEGF family comprises five members namely, VEGF-A, VEGF-B, VEGF-C, VEGF-D and PIGF (Platelet Induced Growth Factor), and that there are three different VEGF receptors (VEGFR), namely VEGFR1, VEGFR2, and VEGFR3. VEGFR1 (Flt-1) binds to VEGF-A, VEGF-B, and PIGF. VEGFR2 (KDR/Flk-1) appears to mediate almost all of the known cellular responses to VEGF and it binds to VEGF-A, VEGF-C, VEGF-D, and VEGF-E. VEGFR3 (Flt4), which mediates lymphangiogenesis, binds to VEGF-C and VEGF-D, but not VEGF-A ([0052]).
Hong establishes that it is known in the art that a VEGFR typically comprises an extracellular domain that is divided into seven immunoglobulin-like domains(domains 1 to 7, D1 to D7). Immunoglobulin- like domains may or may not be involved in protein-protein interaction or binding of other proteins ([0056], Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare recombinant fusion protein from the genus of Hong comprising D2 of VEGFR1 - D3 of VEGFR2 - D2 of VEGFR3 - D3 of VEGFR3 - Fc of human IgG. The rationale for obviousness is "obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success (MPEP § 2143.01(E)). The relevant findings for this rationale are as follows.
(1) At the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem. In the instant case, Hong teaches that there is a need for an agent that can target all members of the VEGF family. Currently, there are several inhibitors in the market that can bind some members of the VEGF protein (e.g. aflibercept and conbercept that binds VEGF- A, VEGF-B, and PIGF and OPT-302 that binds VEGF-C and VEGF-D). However, these inhibitors do not bind to all five members of the VEGF family ([0052]). Therefore, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem.
(2) There had been a finite number of identified, predictable potential solutions to the recognized need or problem. Hong teaches a flowchart depicting the process for preparing and systematically screening polypeptides that can be used to target and to bind to VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PIGF )Figure 19, [0044]). Therefore, there had been a finite number of identified, predictable potential solutions to the recognized need or problem.
(3) One of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success. One of ordinary skill in the art would expect that a fusion protein comprising D2 of VEGFR1 - D3 of VEGFR2 - D1 of VEGFR3 - D2 of VEGFR3 - D3 of VEGFR3 - Fc of human IgG can be made by the process of Hong because it is included in the genus disclosed in that reference. One of ordinary skill in the art would also expect that this fusion protein would bind to all members of the VEGF family because it comprises immunoglobulin-like domains from all three VEGF receptors. Therefore, one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
(4) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. The specification does not include a comparison between instant SEQ ID NO: 12 and the closest embodiment in Hong. Therefore, there is no evidence of unexpected results on record.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103."KSR, 550 U.S. at 421, 82 USPQ2d at 1397.
Therefore, claims 2, 4, 5, 7, and 8 are obvious over the cited art.
Conclusion
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CHRISTINA M MARCHETTI BRADLEY
Primary Examiner
Art Unit 1654
/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
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