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
Applicant’s election without traverse of Group I (i.e., claims 97-111 and 117-120) and Species A (i.e., ephA2, ALCAM, Seq ID Nos: 81 and 82) in the reply filed on 5 March 2025 is acknowledged.
Status of the Claims
Claims 1-96 were originally filed 13 July 2021. The preliminary amendments filed 15 February 2022 and 5 March 2025 have been entered. Claims 112-116 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5 March 2025. Newly amended claims are drawn to non-elected species (i.e., see claims 100, 101, and 105; see Seq ID Nos: 83-87) and are therefore withdrawn. Claims 97-99, 102-104, 106-111 and 117-120 are currently under consideration.
Priority
The instant application claims priority to PCT/US20/13433 (referred to herein as ‘433 PCT) filed 14 January 2020 and U.S. Provisional Application 62/792359 (referred to herein as ‘359 provisional) filed 14 January 2019.
It is noted the ‘359 application does not disclose instantly claimed Seq ID Nos: 81-97 (see ‘359 provisional pg. 68 Table 6; see instant claims 97-11 and 117-120).
Therefore, the priority date for instant claims 97-11 and 117-120 is that of the ‘433 PCT filed 14 January 2020.
Withdrawn Rejections
In view of Applicant amending claims 97 and 106 to recite 6 particular CDRs and remove 80% sequence identity from claim 108 the 35 USC 112(a) (i.e., enablement) rejection of claims 108 and 117-120 is hereby withdrawn.
In view of Applicant amending claim 97 to recite the particular targets of the bispecific antibody and a particular set of 6 CDRs for the ALCAM binding domain the 35 U.S.C. 112(2) (i.e., written description) rejection over claims 97, 99-111, and 117-120 is hereby withdrawn.
In view of Applicant amending the claims to recite particular sequence identifiers the 35 USC 112(b) rejection of claims 108 and 117-120 is hereby withdrawn.
In view of Applicant amending claims 98 to specify the targets the 35 USC 112(d) rejection regarding the “cell surface guide antigen” clause is hereby withdrawn.
In view of Applicant removing references to the antigen densities in claims 99, 100, and 106 the 35 USC 112(d) rejection of claims 99, 100, and 106 is hereby withdrawn.
In view of Applicant amending the claims to specify the bispecific antibody targets EphA2 and ALCAM all prior art rejections under 35 USC 102 and 103 are hereby withdrawn.
In view of Applicant amending claim 97 to disclose both antigen binding targets the non-statutory double patenting rejection of claims 97-100 and 107 is hereby withdrawn.
Maintained Rejections
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.
Claim 98 and 107 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In so far as Applicant is claiming the EphA2 antigen binding domain internalizes EphA2 and the ALCAM antigen binding domain does not internalize ALCAM, Applicant's arguments filed 20 November 2025 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant argues that amending the claims to recite the particular targets EphA2 and ALCAM stratifies the written description requirement (see Remarks para spanning pgs. 10-11). Although the scope of claim 98 and 107 is unclear (see 112b rejection below), it appears that the claims may be intending to encompass a functional subgenus of antibodies that are non-internalizing. However, the state of the art teaches the internalization rates of a target antigen are unique to the binding domain and the change in internalization rate depends on the particular effector domain and it’s particular internalization rate (see Non-final mailed 05/20/2025 para spanning pgs. 9-10). Applicant discloses an EphA2xALCAM bispecific antibody comprising Seq ID Nos: 73, 74, 81, and 82) resulted in the claimed outcome (i.e., wherein EphA2 is internalizing and ALCAM is non-internalizing). Therefore, disclosure of a single specifies is not representative of the genus of antibody comprising 1 of 6 EphA2 binding domains with any ALCAM (e.g., nanobody, or any source), with the non-internalizing function as currently claimed.
Therefore the 35 USC 112(a) rejection (i.e., written description) of claim 98 is hereby withdrawn.
The following objections and rejections are necessitated by amendment.
Claim Objections
Claim 108 is objected to because of the following informalities:
Claim 108 recites, “wherein the VH and VL comprise the sequences” in line 2 and should recite, “wherein the VH and VL of the second antigen binding domain comprise the sequences”.
Appropriate correction is required.
Applicant is advised that should claim 98 be found allowable, claim 107 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. Applicant is advised that should claim 108 be found allowable, claim 120 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof.
Applicant is advised that should claim 106 be found allowable, claim 119 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof.
When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
New Rejections
Claim Rejections - 35 USC § 112(b)
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 97-99, 102-104, 106-111, and 117-120 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.
Claims 97, 106, 117, and 119 are drawn to a bispecific EphA2xALCAM antibody comprising particular pairs of VH and VL regions that specifically bind EphA2. It is unclear if what is recited in the parathesis is a limitation, an alternative name, or an example. For example, claim 97 recites “Seq ID NO: 81 and Seq ID NO: 82 (RYRgerm_102019_15)” and claim 106 recites “Seq ID NO: 73 or Seq ID NO: 75 (3F1)”.
In addition, the claims 97 and 106 are drawn to “all six complementarity determining region (CDRs) of an antibody” (e.g., see claim 97 lines 7-8). The scope of the CDRs is unclear. For example, are the CDRs particular CDRs as disclosed in the specification (e.g., see specification pg. 7 para [0019]), or using a single and specific CDR numbering scheme (e.g., see specification para spanning pgs. 35-36), or using one or more CDR numbering scheme (e.g., see specification pg. 36 para [0093]).
Claims 98 and 107 are drawn to wherein the EphA2 is an internalizing cell surface antigen and the ALCAM is a non-internalizing cell surface antigen. It is unclear if this is an intended outcome of the bispecific antibody binding or alternatively an inherent property of the individual targets independent of the bispecific antibody.
Claim 99 is drawn to particular VH and VL sequences of the EphA2 binding domain. It is unclear if the language of claim 99 is intended to limit the EphA2 binding domain to comprise Seq ID Nos: 81 and 82, or alternatively, the language is intended to limit the sequences from which the CDRs are selected from (see claim 97 lines 6-7). For the same reasons claims 108, 118, and 120 are also unclear.
Claim 106 and 119 are drawn to limitations in the second antigen binding domain. The language of claim 106 recites, “the VH and VL respectively comprise the sequences of:” (see line 4) and, for example, “Seq ID Nos: 73 or Seq ID No: 75 (3F1)” (see line 6). It is unclear of the second antigen binding domain requires both Seq ID No: 73 and 75 as suggested by line 4, or alternatively, requires either Seq ID No: 73 or 75 as suggested in line 6.
Claim 117 is drawn to wherein an engineered antibody comprises Seq ID No: 887 (see part (d)); however the sequence listing only has 110 sequences.
Claim Rejections - 35 USC § 112(d)
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.
Claims 98 and 107 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.
Claims 98 and 107 are drawn to wherein EphA2 is an internalizing antigen and ALCAM is a non-internalizing antigen. Claims 98 and 107 do not further limit the structure of the bispecific antibody claimed in independent claim 97. EphA2 is known in the art as an internalizing antigen while ALCAM is known as a non-internalizing antigen (see Lee as cited on the PTO-892 mailed 10/07/2024, pg. 6 last para).
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 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 117 and 118 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2016007741 A1 (referred to herein as Lui), as evidenced by WO2005070963 A1 (referred to herein as Allan).EphA2 antibody HCA-F1 possess the most robust internalization properties of DU145 cells (i.e., human prostate cancer) (see Lui pg. 75 para [0340], pg. 77 para [0343], table 2). Lui demonstrated the anti-EphA2 HCA-F1 antibody conjugated to saporin effectively had potent cytotoxicity against DU145 cells but not control LNCAP (i.e., EphA2 negative) cells (see Lui pg. 84 para [0345], figure 9). In addition, the anti-EphA2 antibody HCA-F1 conjugated to MMAF via a MC-vcPAB linker also effectively killed DU145 cells in vitro (see Lui pg. 88 para [0353]). It is noted, the anti-EphA2 antibody HCA-F1 comprises Seq ID Nos: 2 and 6 which comprises CDRs identical to the Kabat CDRs of instantly claimed Seq ID Nos: 81 and 82 (elected) as evidenced by Allan (see Lui pgs. 26-27, Table 1; see Allan pg. 79 Table 6; see sequence comparison below). It is noted claim 118 is drawn to wherein the 6 CDRs are selected from Seq ID Nos: 81 an 82. This is pertinent to instant claims 117 and 118.
Claim Rejections - 35 USC § 103
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 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
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.
Claims 97-99, 102-104, 107, and 109-111 are rejected under 35 U.S.C. 103 as being unpatentable over Konterman (see Konterman (2012) Dual Targeting strategies with bispecific antibodies, mAbs, 4:2, 182-197), WO2016007741 A1 (referred to herein as Lui), and US Patent Publication 2010/0233165 (referred to herein as Marks) as evidenced by WO2005070963 A1 (referred to herein as Allan).
Konterman treatment with single target agents for complex diseases such as cancer or inflammatory disorders is limited due to their multifactorial nature (see Konterman pg. 182 para spanning cols. 1-2). One strategy for overcoming these limitations is blockade of multiple targets on one target by either combinations of multiple single target agents or dual targeting with bispecific antibodies (see Konterman pg. 182, 2nd col. last para, pg. 183, 1st col. 1st full para). The advantage of the latter being development is less complex for development and patient treatment (see Konterman pg. 183, 1st col. 1st full para). Dual targeting strategies are divided into two categories: i. those that directly act on target structures and ii. delivery of therapeutically active moiety (see Konterman pg. 183 para spanning cols. 1-2). Konterman teaches several bispecific antibodies directed to a variety of targets on the same cell (see Konterman pg. 183 table 1) as well as conjugated to toxins or carrier systems (see Konterman pg. 184 Table 2). Dual targets can be both independent or dependent (see Konterman pg. 184, 1st col., 1st para). Studies have shown, in general, bispecific antibodies outperform treatment with monospecific antibodies, but are similar to the combination of parental antibodies and targeting different disease modulators has improvement over the standard therapy (see Konterman pg. 193, 2nd col. last para).
Lui teaches ideal antibody drug conjugates should be capable of both tumor-selective binding and efficient endocytosis (see Lui pg. 67 para [0323]). EphA2 antibody HCA-F1 possess the most robust internalization properties of DU145 cells (i.e., human prostate cancer) (see Lui pg. 75 para [0340], pg. 77 para [0343], table 2). Lui demonstrated the anti-EphA2 HCA-F1 antibody conjugated to saporin effectively had potent cytotoxicity against DU145 cells but not control LNCAP (i.e., EphA2 negative) cells (see Lui pg. 84 para [0345], figure 9). In addition, the anti-EphA2 antibody HCA-F1 conjugated to MMAF via a MC-vcPAB linker also effectively killed DU145 cells in vitro (see Lui pg. 88 para [0353]). Lui teaches, “functional evidence for rapid internalization by out anti-EphA2 antibody IgG HCA-F1 and demonstrated potential for the development of targeted therapeutics against EphA2-positive tumors” (see Lui pg. 84 para [0345]). It is noted, the anti-EphA2 antibody HCA-F1 comprises Seq ID Nos: 2 and 6 which comprises CDRs identical to the Kabat CDRs of instantly claimed Seq ID Nos: 81 and 82 (elected) as evidenced by Allan (see Lui pgs. 26-27, Table 1; see Allan pg. 79 Table 6; see sequence comparison below). Lui also claims wherein the immunoconjugate is attached to an effector wherein the effector is a second antibody (see Lui claim 57).
Marks discloses antibodies targeting internalizing tumor epitopes could be exploited to achieve efficient and specific intracellular delivery of chemotherapeutic drugs and/or other tumor modulating agents (see Marks pg. 1 para [0005]). Anti-ALCAM antibodies, UA20 and 585II41 possess internalizing functions that can be exploited for targeted payload delivery and bound both PC3 and DU-145 cell lines (see Marks pg. 26 para [0224-0226], pg. 28 para [0234]). Both antibodies conjugated to maleimide-activated liposomes were efficiently endocytosed by both PC3 and DU145 cells (see Marks pg. 28 para [0232]). The invention encompasses wherein the anti-ALCAM antibodies are conjugated to a Saponaria officinalis inhibitor (e.g., saporin), a second antibody, or a cytotoxin (see Marks claim 14 and 37, pg. 21 para [0150]). Specifically, Marks discloses “These antibodies are candidates for the development of targeted therapeutics against prostate cancer” (see Marks pg. 28 para [0232]) and “UA20 is an excellent candidate for imaging and/or therapy” (see Marks pg. 30 para [0249]).
Therefore, an ordinary artisan would combine the ephA2 HCA-F1 immunoconjugate (i.e., saporin or MC-vcPAB) taught by Lui with the ALCAM UA20 antibody taught by Marks given the advantages of bispecific tumor targeting antibodies taught by Konterman. Specifically, reduced complexity in development and treatment along with bispecific antibodies in general outperform their monospecific counterparts. There is a reasonable expectation of success given the success of several dual targeting antibodies with several different tumor targeting antigens. This is pertinent to instant claims 97 102, and 117.
The language of claims 98 and 107 are related to a functional property of the target antigens themselves. Therefore, claims 98 and 107 do not limit the scope of the claim and are included in the rejection. To put another way, the fact that ALCAM may not normally be recycled from the plasma membrane on its own, i.e., it is non-internalizing, does not further limit the structure or function of an antibody that binds ALCAM. Any antibody that binds ALCAM is within the scope of claim 98 whether the antibody causes internalization of ALCAM or not, since the limitations are merely an inherent property of ALCAM itself.
Claim 99 is drawn to wherein the CDRs are selected from Seq ID Nos: 81 and 82. Therefore, the anti-EphA2 antibody taught by Lui comprising Seq ID Nos: 2 and 6 is which the scope of claim 99.
Regarding claim 103 wherein the moiety-of interest is conjugated to a functional fragment. Lui teaches the anti-EphA2 antibody/immunoconjugate is an FC fusion (see Lui pg. 22 para [0157, 0158], pg. 38 para [0215]).
Regarding claim 104 wherein the mean number of MOIs is 1-20, Lui teaches the anti-EphA2 antibody conjugated with MC-vc-PAB. Therefore, it necessarily follows that at least one MMAF molecule was conjugated to the antibody.
Regarding claim 109-111 Lui discloses the invention encompasses DNA sequences encoding the fusion protein, a host for expression, (e.g., E. coli), and pharmaceutical compositions (see Lui pgs. 53-54 para [0272], pg. 54 para [0278], pg. 55 para [0279], pg. 56 para [0283, 0284]).
Claim 97-99, 102-104, 107, and 109-111 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent Publication 2017/0007715 A1 (referred to herein as Andreev as cited on the PTO-892 mailed 05/20/2025) published 12 January 2017, WO2016007741 A1 (referred to herein as Lui), and Piazza (as cited on the PTO-892 mailed 05/20/2025), Tomita (see Tomita et al. (2000) Coordinate Recruitment of E-cadherin and ALCAM to cell-cell contacts by α-catenin) Biochemical and biophysical research communications, Vol. 267, Iss. 3, pgs. 870-874) as evidenced by Allan.
Andreev discloses a multispecific antigen binding molecule comprising a first antigen binding domain that binds a target molecule and a second antigen binding domain that binds an internalizing effector protein wherein the simultaneous binding of the target and internalizing effector results in the attenuation of the activity of the target molecule to a greater extent than the binding of the target molecule alone (see Andreev abstract, pg. 1 para [0005], figure 1A). Specifically, Andreev discloses the multispecific antigen binding domain is able to attenuate the activity of the target to a greater extent than monospecific agents due to the simultaneous binding of the target and effector (see Andreev pg. 1 para [0005]). The internalizing effector Protein is defined as a protein that is capable of being internalized into a cell or that otherwise participates in or contributes to retrograde membrane trafficking (see Andreev pg. 6 para [0059]). The target is defined as any protein, polypeptide, or other macromolecule whose activity or extracellular concentration is desired to be attenuated, reduced or eliminated (see Andreev pg. 7 para [0066]). The invention encompasses wherein the target is a tumor associated antigen and is conjugated to a drug, toxin, radioisotope, or other substance (see Andreev pg. 9 para [0078, 0080]). As a proof of concept Andreev discloses a bispecific Kremen-2 (i.e., internalizing effector) Fc-receptor (i.e., target molecule) was able to effectively internalize via Kremen-2 the cell surface Fc-receptor target (see Andreev pg. 11 para [0094, 0095]). Additional experiments disclose multispecific binding agents directed to i. IL-4R (i.e., target) and CD63 (i.e., internalizing effector), ii. SOST (i.e., target) and CD63, iii. LPS (i.e., target) and CD63, and iv. Her2 (i.e., target) and PRLR (i.e., internalizing effector protein) have decreased target signaling dependent on the internalizing effector (see Andreev pg. 12 para [0106-0107] (IL4RxCD63), pg. 13 para [0111] (SOSTxCD63); pg. 13 para [0118] (LSPxCD63), pg. 14 para [0127] (Her2xPRLR)).
The teachings of Lui are set forth above. Briefly, Lui discloses EphA2 HCA-F1 comprising identical Kabat CDRs as instantly claimed Seq ID Nos: 81 and 82 as evidenced by Allan (see above) which is rapidly internalizing into prostate cancer cells (see above). It is noted Lui discloses using the EphA2 antibody to treat metastatic melanoma (see pg. 14 para [0117, 0120, 0121]).
Piazza discloses a human ALCAM scFv (i.e., I/F8) with kinetic slower internalization kinetics than transferrin (see Piazza abstract, pg. 1516, 1st col. 3rd para, pg. 1520, 1st col. 1st para). Despite the slower internalization kinetics the (I/F8) scFv an ADC comprising I/F8 conjugated to saporin was able to selectively kill ALCAM positive cell lines (see Piazza abstract, pg. 1522, Table 3). Pizza shows that at 10 minutes there is next to no internalization of the ALCAM scFv whereas transferrin has been highly internalized (see Piazza figure 4, panel A, in particular 10ʹ, Figure 8C-E). Few small vesicles can be seen at the cell surface at 30 minutes which Pizza suggests are the internalized vesicles, with more pronounce stanning at 60 minutes (see Piazza figure 4, panel A, pg. 1519, 2nd col. last para). It is noted Lui shows anti-epha2 HCA-F1 antibody showed almost immediate internalization with very low amounts of detectable IgG on the surface after 90 minutes (see Lui pg. 75 para [0340]). The 1/F8 scFv also binds across different species and competes with the soluble ligand (see Piazza pg. 1523, 2nd col. 2nd para). Piazza suggests the ability of 1/F8 to block CD6/ALCAM interactions may provide a useful tool to interfere in ALCAM functions and analyze its functional role in metastatic processes (see Piazza pg. 1523, 2nd col. 3rd para). ALCAM has been shown to be involved in the process of cell spreading, for example, metastatic behavior of different tumors such as melanoma (see Piazza pg. 1523, 2nd col. 3rd para).
Tomita discloses, “in melanoma cell lines ALCAM is exclusively expressed in the highly metastatic cell lines, suggesting that ALCAM expression may correlate with malignant potential (see Tomita pg. 870, 2nd col.). In addition, Tomita discloses a correlation between cadherin-mediated adhesion and the expression pattern of ALCAM in human prostate cancer cells. Specifically, DU-145 cells lines show functional e-cadherin mediated adhesion and ALCAM expression is seen at cell-cell contacts (see Tomita pg. 874, 1st col. 1st full para).
Therefore, the ordinary artisan would combine the anti-EphA2 HCA-F1 ADC taught by Lui with the I-F8 ALCAM scFv in order to attenuate the slow internalization of the ALCAM target with the rapid internalization of EphA2 (i.e., internalizing effector) as taught by Andreev given Tomita discloses a functional role for ALCAM in Du-145 cells (i.e., prostate cancer) and Lui teaches the anti-EphA2 HCA-F1 antibody is rapidly internalized into the same cancer cell line. Piazza discloses the I-F8 ALCAM scFv has a significantly slower internalization rate compared to other known internalizing proteins (i.e., transferrin receptor). There is a reasonable expectation of success given Andreev teaches the broader concept of modulating internalization of target protein by an effector is applicable across different targets (e.g., Her2, LRP, SOST, and IL-4R) and different internalizing effectors (e.g., CD63 and PRLR).
The language of claims 98 and 107 are related to a functional property of the target antigens themselves. Therefore, claims 98 and 107 do not limit the scope of the claim and are included in the rejection. To put another way, the fact that ALCAM may not normally be recycled from the plasma membrane on its own, i.e., it is non-internalizing, does not further limit the structure or function of an antibody that binds ALCAM. Any antibody that binds ALCAM is within the scope of claim 98 whether the antibody causes internalization of ALCAM or not, since the limitations are merely an inherent property of ALCAM itself.
Claim 99 is drawn to wherein the CDRs are selected from Seq ID Nos: 81 and 82. Therefore, the anti-EphA2 antibody taught by Lui comprising Seq ID Nos: 2 and 6 is which the scope of claim 99.
Regarding claim 103 wherein the moiety-of interest is conjugated to a functional fragment. Lui teaches the anti-EphA2 antibody/immunoconjugate is an FC fusion (see Lui pg. 22 para [0157, 0158], pg. 38 para [0215]).
Regarding claim 104 wherein the mean number of MOIs is 1-20, Lui teaches the anti-EphA2 antibody conjugated with MC-vc-PAB. Therefore, it necessarily follows that at least one MMAF molecule was conjugated to the antibody.
Regarding claim 109-111 Lui discloses the invention encompasses DNA sequences encoding the fusion protein, a host for expression, (e.g., E. coli), and pharmaceutical compositions (see Lui pgs. 53-54 para [0272], pg. 54 para [0278], pg. 55 para [0279], pg. 56 para [0283, 0284]).
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 117 and 118 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,702,480 B2 (referred to herein as Pat ‘480). Although the claims at issue are not identical, they are not patentably distinct from each other.
Applicant's arguments filed 20 November 2025 have been fully considered but they are not persuasive. Applicant has requested double patenting be held in abeyance until allowable subject matter is found (see Remarks pg. 16 last para).
The ‘480 patent is drawn to an ephA2 antibody comprising Seq ID No: 121 which has identical Kabat CDRs of the instantly claimed EphA2 antibody (see instant claims 117 and 118).
Sequence Comparison
(Qy) Instant Seq ID No: 81 compared (Db) to Lui Seq ID No: 2
*solid black underline are Kabat CDR numbering as evidenced by Allan
PNG
media_image1.png
396
719
media_image1.png
Greyscale
(Qy) Instant Seq ID No: 82 compared to (Db) Lui Seq ID No: 6
(Qy) Instant Seq ID No: 81 compared to (Db) US Patent ‘480 Seq ID No: 121
*solid black underline are Kabat CDR numbering as evidenced by Allan
PNG
media_image2.png
267
535
media_image2.png
Greyscale
(Qy) Instant Seq ID No: 82 compared to (Db) US Patent ‘480 Seq ID No: 121
PNG
media_image3.png
276
532
media_image3.png
Greyscale
Conclusion
No claim allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/H.A.P./Examiner, Art Unit 1644
/AMY E JUEDES/Primary Examiner, Art Unit 1644