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/Restriction
Applicant’s election without traverse of Invention II and/or species PEG, L1, L1 is valine, maleimide, and SEQ ID NO: 45, in the reply filed on 11AUG2025 is acknowledged.
Per the interview with Applicant on 04FEB2026, the election of species of valine for L1 was clarified. To facilitate prosecution, Applicant suggested limiting the structures of original claim 12 to the four structures of original claim 17, wherein the reactive group is maleimide, the X group is PEG4, and L1 is selected from Val-Cit-PAB, Asn-Ala, Val-Ala, or none. Examiner noted that for initial search purposes the structures would be limited to Val-Ala or Val-Cit-PAB (i.e., new claim 45). Additionally, upon further consideration the requirement for an election of species of SEQ ID NO: 45 as set forth in the restriction requirement mailed on 10APR2025 is hereby withdrawn.
In conclusion, the restriction to Invention II and the species election of the reactive group being maleimide, the X group being PEG4, and L1 being selected from Val, Val-Cit, Val-Cit-PAB, Val-Ala, Val-Ala-PAB, etc. are maintained. Therefore, new claim 60 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Election was originally made without traverse in the reply filed on 11AUG2025.
Claim Status
Applicant’s amendments received 13FEB2026 are acknowledged.
Claims 1-44 have been canceled.
Claims 45-60 are new.
Claims 45-60 are pending in the instant application (i.e., Claim(s) 45 is/are independent).
Claim 60 remains withdrawn.
Claims 45-59 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/EP2020/067210, filed 19JUN2020, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of GB 1908886.3 filed on 20JUN2019 has been received and is acknowledged.
Nucleotide and/or Amino Acid Sequence Disclosures
Examiner notes that the specific deficiencies of (GGGGS)3 and (GGGGS)5; located on p 37, line 6; p 16, line 12; p 46, line 2 of the clean specification filed 03APR2025 are withdrawn; However, Applicant’s submission of a new CRF filed 13FEB2026 and upon further consideration of the specification additional sequence deficiencies are noted.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The ASCII .txt file purported to contain the computer readable form (CRF) copy of the "Sequence Listing" filed with this application in accordance with 37 CFR 1.821(c)(1) has been found to be damaged, unreadable, or otherwise contains an error as indicated on document "Computer Readable Form (CRF) for Sequence Listing - Defective" dated 13FEB2026.
Required response – Applicant must provide:
a replacement "Sequence Listing" in the form of an ASCII plain text file under 37 CFR 1.821(c)(1) as provided for in 37 CFR 1.825(b)(1)(i), together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(b)(3);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
OR
A "Sequence Listing" part of the disclosure, as described above in item 1 c) or 1 d) as provided for in 37 CFR 1.825(b)(1)(ii) or 1.825(b)(1)(iii); together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
When the "Sequence Listing" part of the disclosure is submitted according to item 1 c), or 1 d) above, Applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) as required by 37 CFR 1.825(b)(6); and
a statement according to item 2) a) or b) above.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d) (see for example p 7, lines 10-14 of the marked-up copy filed 13FEB2026).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located on p 7, lines 10-14 of the marked-up copy filed 13FEB2026.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Claim Objections
Applicant’s arguments, see p 10, Claim objections section, filed 13FEB2026, with respect to objections to claim(s) 12, 22-25, 30-31, and 41 for informalities are moot because claims 12, 22-25, 30-31, and 41 have been cancelled.
Withdrawn Rejections
Indefiniteness
Applicant’s arguments, see p 10, Rejections under 35 USC §112(b) section, filed 13FEB2026, with respect to the rejection(s) of claim(s) 12, 14-15, 22-26, 30-34, 41, and 44 are moot because claims 12, 14-15, 22-26, 30-34, 41, and 44 have been cancelled.
Enablement and Written Description
Applicant’s arguments, see p 10-11, Rejections under 35 USC §112(a) section, filed 13FEB2026, with respect to the rejection(s) of claim(s) 12, 14-15, 22-26, 30-34, 41, and 44 are moot because claims 12, 14-15, 22-26, 30-34, 41, and 44 have been cancelled.
35 USC §102
Applicant’s arguments, see p 11, Rejections under 35 USC §102 section, filed 13FEB2026, with respect to the rejection(s) of claim(s) 12, 14-15, 23-24, and 44 are moot because claims 12, 14-15, 23-24, and 44 have been cancelled.
35 USC §103
Applicant’s arguments, see p 11, Rejections under 35 USC §103 section, filed 13FEB2026, with respect to the rejection(s) of claim(s) 12, 14-15, 23, 41, and 44 are moot because claims 12, 14-15, 23, 41, and 44 have been cancelled.
Double Patenting
Applicant’s arguments, see p 11, Double patenting rejections section, filed 13FEB2026, with respect to the rejection(s) of claim(s) 12, 14-15, 22-26, 30-34, and 44 are moot because claims 12, 14-15, 22-26, 30-34, and 44 have been cancelled.
Applicant’s arguments, see p 12, Double patenting rejections section, filed 13FEB2026, with respect to the provisional rejection(s) of claim(s) 12, 14-15, 22-26, and 30-34 are moot because claims 12, 14-15, 22-26, and 30-34 have been cancelled.
Claim Rejections - 35 USC § 112
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.
Applicant’s claim amendments received as part of the 13FEB2026 response have necessitated the following new grounds of rejection.
Claims 45 and 54 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 45 and 54 appear to recite a Markush group, but the group of alternatives are not closed as required by a proper Markush group in MPEP §2173.05(h). In this instance, claims 45 and 54 (i.e., CDR1, HC2, HV4, and CDR3 sections) recite Markush-type claims without reciting proper Markush-type language such as “selected from the group consisting of” and an “and” between the last two species. For example, in claim 45, an “and” is missing between structure three and structure four. Claim 54 has the same issue.
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.
Applicant’s claim amendments received as part of the 13FEB2026 response have necessitated the following new grounds of rejection.
Written Description
Claims 45-59 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.
Scope of the claimed genus:
Applicant has broadly claimed a target-binding molecule-drug conjugate comprising a singular anthracycline (PNU) derivative linked to a cysteine of essentially any specific antigen binding protein, wherein the structures are selected from:
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. The broadest claims do not require the target-binding molecule-drug conjugate to have any function apart from binding a specific antigen, with dependent limitations adding additional functional limitations, such as, binding ROR1 (i.e., claim 47 and 49), not binding ROR2 (i.e., claim 50), binding both human and murine ROR1 (i.e., claim 51), binding deglycosylated ROR1 (i.e., claim 52), not binding to a linear peptide selected from the group consisting of SEQ ID NOs: 34, 35, 36, and 37 (i.e., claim 53), or binds to humanized or de-immunized ROR1 (i.e., claim 57). No claims recite any specific or particular structure of the target-binding molecule-drug conjugate apart from claims 46, 48, 54, 56, and 58 (partially). Specifically, claim 46 recites that the antigen binding protein is selected from Ig or ab, Ig Fc, Ig Fab, Fab’, etc.; however the claim does not provide a specific antigen binding domain structure; claim 48 recites that the antigen binding protein has the structure of FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4, but does not provide a specific antigen binding domain structure; claim 54 recites a variety of SEQ ID NOs for CDR1, HV2, HV4, and CDR3, resulting in 360 combinations of ROR1 specific antigen binding molecules, of which only 12 combinations are supported in claim 56; claim 55 recites a variety of SEQ ID NOs for FW1, FW2, FW3a, FW3b, FW4, however, no antigen binding domain structure is provided; claim 56 recites 12 specific VNAR binding structures of essentially infinite numbers of ROR1-specific binding proteins; and claim 58 recites an antibody that binds HER2, trastuzumab or a derivative thereof, however there is only support for trastuzumab with a S442C mutation, rather than any HER2 specific antigen binding protein as currently claimed. Claim 59 is also rejected since it depends on claim 46, which depends on claim 45, but does not remedy these deficiencies.
State of the relevant art:
Generally, the prior art has recognized that antibodies in antibody drug conjugates require internalization to be effective drug vehicles. Chalouni teaches antigen binding, the anti-tumor potency of cytotoxic drugs and the favorable pharmacokinetic profile of the antibody are critical for the function of the ADC (Chalouni, et al., J Exp Clin Canc Res, 2018, 37, 1-12, herein referred to as “Chalouni”, see p 3, left column, ¶3). In addition, Chalouni teaches the efficacy of an ADC also relies on its internalization and processing, the release of the drug from the intracellular compartment to the cytosol and binding to its intracellular target to trigger cell death (p 3, left column, ¶3). Specifically, Chalouni teaches that ADC trafficking and processing in a classic model wherein: The ADC 1) binds to its surface antigen and 2) the complex is internalized, 3) it reaches lysosomes where its linker of the ADC is degraded leading to the release of the drug, 4) the drug passes from the intracellular compartment to the cytosol, and 5) binds to its target, DNA or tubulin resulting in apoptosis (Fig. 1b) and/or after release of the drug in the cytosol that the drugs may also be 6) effluxed into the microenvironment via pumps or passive transfer through the cell membrane and 7) enter a neighbor cancer cell resulting in the bystander effect (Fig. 1c).
The prior art further teaches that antibody drug conjugates can have unpredictable effects when combined, wherein the drug can affect antibody trafficking. Chalouni teaches that while the design of an ADC may rely on features specific to the trafficking of the parent antibody, this strategy can be challenging as the addition of a drug can result in subtle differences in these antibody properties such as preventing or inducing the internalization of a construct as seen for anti-CD19 antibody (p 4, left column, last paragraph). Thus, antibody internalization is a requirement for an effective ADC and drugs may cause unpredictable effects on ADC internalization. Therefore, any antibody would not be expected to lead to an effective ADC.
With regard to antibodies, it should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway, et al., Immunobiology: The Immune System in Health and Disease, 5th edition, 2001, section 3.6). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff, et al., PNAS, 1982, 79, 1979-1983 see entire document, particularly the abstract and the middle of the left column of p 1982). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
Artisans are well aware that knowledge of a given antigen (for instance essentially any antigen or epitope or a specific epitope of ROR1, but not ROR2 or human ROR1 and murine ROR1 or deglycosylated ROR1) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (Edwards, et al., J Mol Biol, 2003, 334, 103-118, see entire document). Goel et al. disclose the synthesis of three monoclonal antibodies that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (Goel, et al., J Immunol, 2004, 173, 7358-7367, see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., J Biol Chem, 1995, 270, 18067-18076, see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably represent the breadth of the genus of antibodies that bind the given antigen in the instant application.
In the instance of single domain antibodies, the formation of an intact antigen-binding site requires the association of three CDRs or CDR1, HV2, HV4, and CDR3 for VHH or VNARs, respectively (rather than the six present in conventional VH/VL antibodies (Henry, et al., MAbs, 2018, 10, 815-826, and Barelle, et al., Antibodies, 2015, 4, 240-258, see entire documents). Barelle further teaches that the primary focus for creating library diversity has been through the comprehensive mutagenesis of CDR3, as it is this loop that is believed to play a central role in antigen recognition and binding; however, the HV loops can also contribute not only to increased affinity of binding through increased interface interactions but can also bind a target independently (Barelle, p 249). Therefore, the specific combination of CDR1, HV2, HV4, and CDR3 affects structure within the VNAR and specific antigen binding. Thus, based upon the prior art, skilled artisans would reasonably understand that it is the organization of the two CDRs and two HV regions in combination, in a VNAR, which gives rise to the functional property of antigen binding.
Gordon teaches that the CDR3 loop contributes most to sdAb-antigen binding specificity and is typically longer than the CDR-H3 loop of a conventional antibody (Gordon, et al., Front Immunol, 2023, 14, 1-18, see entire document). Asaadi, et al., teach that the sdAbs evolved with an extra disulfide bond between CDR1, CDR2, or FR2, which in addition to the other structural features of a sdAb increases paratope diversity and allows for a wide variety of geometrical loop structures that deviate fundamentally from the canonical loop structures defined for conventional antibodies (Asaadi, et al., Biomarker Res, 2021, 9, 1-20, see entire document). Therefore, the specific combination of CDRs 1-3 or CDR1-HV2-HV4-CDR3 affects structure within the sdAb and specific antigen binding. Thus, based upon the prior art, skilled artisans would reasonably understand that it is the organization of the three CDRs or CDR1-HV2-HV4-CDR3 in a specific combination, in a single domain antibody, which gives rise to the functional property of antigen binding to in this instance, essentially any epitope or ROR1.
Description of representative species in the specification:
MPEP § 2163 states that “a representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
To support such broad claims, the specification teaches five anti-ROR1 VNAR antibodies (i.e., B1, P3A1, D3, E9, and 2V clones) linked via SEQ ID NO: 60 to a human IgG1 Fc domain comprising a S239C substitution (EU numbering) and a modified (i.e., S442C substitution in the Fc domain) anti-HER2 (i.e., trastuzumab) wherein the cysteine substitution in the Fc region are used to conjugate via a maleimide the linker-drug conjugates of for example claim 45 (p 36-46). Additionally, the structures of claim 45, suggest that a single anthracycline derivative is attached to the specific antigen binding protein; but only trastuzumab and P3A1 h Fc(442) correspond to DAR of 1 (Table 4b and Table 8). However, given the immense breadth of the claims and the depth and diversity of the antibody repertoire as described above, such a disclosure would not reasonably be considered representative of the genus: a target-binding molecule-drug conjugate comprising essentially any specific antigen binding protein and an anthracycline derivative, which is only described by its binding target.
Identifying characteristics and structure/function correlation:
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi, (Fed Cir, 2017-1480. 10/5/2017). In Amgen v. Sanofi, the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e., the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it. As such, knowledge of where an antibody binds provides no information as to what such an antibody necessarily looks like (i.e., its primary amino acid structure).
It should also be noted that the USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018. See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. This Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies and states: “In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.” Further, the courts have indicated that the enablement and written description requirements of 35 USC 112 are separable as can be seen in for example Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111.
To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed antigen binding activity.
The specification discloses five clones which bind ROR1, linked to a modified Fc region (i.e., S239C) and are not attributed to specific CDR1, HV2, HV4, and CDR3 sequence combinations of the 360 potential combinations of claim 54 or specific VNAR sequences of the potential 12 sequences of the essentially infinite number of ROR1-specific binding proteins of claim 56 (p 36-46). Furthermore, the only additional construct is a S442C-Fc domain-modified trastuzumab, wherein the Fc modification is different from the Fc modification of the ROR1 species (p 46).
Claim analysis:
In this instance, the prior art supports a specific combination of antigen binding protein and drug in an ADC-like construct; that the antigen binding protein must be defined by a specific structure, for example if it is an antibody a specific combination of six nondegenerate CDRs are required and if it is a VNAR, a specific combination of three nondegenerate CDRs or CDR1, HV2, HV4, and CDR3 are required rather than by the target antigen or epitope; and that the art for both antibody constructs and ADC-like constructs lack predictability. As presently written, the claims recite that the four structures of claim 45 function to bind essentially any antigen. However, the specification and working examples fails to disclose the breadth of structures (i.e., any antigen binding protein or any ROR1-specific antigen binding protein, wherein a specific combination of six nondegenerate CDRs for antibody-like structures or three nondegenerate CDRs or CDR1, HV2, HV4, and CDR3 for VNAR constructs) encompassed by the language of the instant claims will have the same function (i.e., binding any antigen or binding ROR1). Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of essentially any antigen binding protein within the target-binding molecule-drug conjugate that function to bind as defined by the target rather than being attributed to specific sequences, at the time the instant application was filed.
Applicant argues that the specification provides a representative number of species with the scope of the genus of structural features are common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus (p 10-11, Rejections under 35 USC §112(a) section).
RESPONSE
Applicant’s arguments have been fully considered but are found non-persuasive essentially for the reasons of record and as described supra.
As set forth in the rejection of record, the specification provides neither a representative number of the encompassed target-binding molecule-drug conjugate comprising essentially any antigen binding protein, nor does it provide a descriptive of structural features that are common to the encompassed target-binding molecule-drug conjugate.
Therefore, because the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the artisan cannot envision the detailed structure of the encompassed target-binding molecule-drug conjugate and therefore Applicant was not in possession of the instant claimed invention.
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.
Applicant’s claim amendments received as part of the 13FEB2026 response have necessitated the following new grounds of rejection.
Claims 45-57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-57 of U.S. Patent No. 12,324,837 B2, herein referred to as “’837” in view of US 2018/0360985 (Zhu, et. al, 20DEC2018), herein referred to as “’985” and Cazzamalli, et al., (ACS Omega, 2018, 3, 14726-14731), herein referred to as “Cazzamalli.”
The issued claims of the ‘837 patent recite: A ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (II), wherein FW1 is a FW region, CDR1 is a CDR sequence of SEQ ID NO: 1, etc., wherein the terminal X and Y are optional amino acid sequences; and wherein the specific antigen binding molecule is conjugated to a second moiety (i.e., claim 42). The specific antigen binding molecule of claim 42, wherein the conjugation is via a cysteine residue in the amino acid sequence of the specific antigen binding molecule; or wherein the conjugation is via a thiol, aminooxy, or hydrazinyl moiety incorporated at the N- or C-terminus of the amino acid sequence of the specific antigen binding molecule; or wherein the second moiety is selected from the group comprising a detectable label, dye, toxin, drug, pro-drug, radionuclide, or biologically active molecule; or wherein the second moiety is at least one toxin selected from the group consisting of maytansinoids,…anthracycline, PNU-derived anthracyclines,…and pyridinobenzodiazepines; or wherein the ROR1-specific antigen binding molecule does not bind to ROR2; or wherein the ROR1 specific antigen binding molecule binds to both human ROR1 and murine ROR1; or wherein the ROR1 specific antigen binding molecule binds to deglycosylated ROR1; or wherein the ROR1 specific antigen binding molecule does not bind to a linear peptide sequence selected from SEQ ID NOs: 34-37; or wherein the FW1 is 20 to 28 amino acids, FW2 is 6 to 14 amino acids, FW3a is 6 to 10 amino acids, FW3b is 17 to 24 amino acids, and FW4 is 17-24 amino acids; or wherein FW1 is selected from SEQ ID NOs: 19-24, FW2 is selected from SEQ ID NOs: 25-26, FW3a is selected from SEQ ID NO: 27-28, FW3b is selected from SEQ ID NO: 29-31, and FW4 is selected from SEQ ID NO: 32-33; or wherein the ROR1 specific antigen binding molecule comprises SEQ ID NO:43 (i.e., 100% query match to SEQ ID NO: 43 of the instant application, OA.APPENDIX); or wherein the binding molecule is humanized; or wherein the binding molecule is de-immunized (i.e., claims 44-57, respectively).
In this instance, because claim 48 of the ‘837 patent is silent on the linker between the maleimide and the PNU-derived anthracycline, the specification was consulted to determine the scope of the structures claimed. Per the specification of the ‘837 patent the mal-linker-drug encompasses mal-PEG4-val-cit-PAB-DMEDA-PNU159682, wherein DMEDA is N,N’-dimethylethylenediamine (i.e., methyl groups on each amine, rather than hydrogens):
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(Fig 32).
However, they do not claim: the ethylenediamine between the PABC and drug.
Nevertheless, ‘985 teaches antibody drug conjugates, wherein the drug is selected from D1, D2, etc., and combinations thereof. The structure of D2 is:
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. In this instance the PNU derivative is modified with an ethylenediamine for reaction with the remainder of the linker of maleimide-PEG4-val-cit-PAB-PNP as synthesized in Cazzamalli:
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(section 4.2.2).
It would have been obvious to artisans to modify the issued products of an anti-ROR1 VNAR ADC utilizing thiol conjugation to the N- or C-terminus of the binding molecule and a PNU anthracycline derivative (i.e., maleimide-PEG4-Val-Cit-PAB-DMEDA-PNU159682 as claimed by the ‘837 patent to exchange the DMEDA-PNU159682 for EDA-PNU159682, as taught by ’985 and Cazzamalli. This is because both ethylenediamine (EDA) and N,N’-dimethylethylenediamine are frequently used as viable linker flanks to the self-immolative PABC because in combination they facilitate cyclization and payload (i.e., drug) release. One would have been motivated to do so, given the direction by the ‘837 patent that the anti-ROR1 VNAR could be linked to generally any PNU anthracycline derivative via a thiol reactive moiety (i.e., maleimide) with no limitations on the linker and furthermore, upon consultation of the specification to determine the scope of the claimed ADC of the ‘837 patent, the maleimide-PEG4-Val-Cit-PAB-DMEDA-PNU159682 structure is found to be an obvious variant of maleimide-PEG4-Val-Cit-PAB-EDA-PNU159682 as disclosed by ’985 and Cazzamalli. There would have been a reasonable expectation of success, given the knowledge that by modifying the anti-ROR1 VNAR ADC, wherein the PNU anthracycline derivative drug is conjugated to a thiol at the N- or C-terminus or has the structure of maleimide-PEG4-Val-Cit-PAB-DMEDA-PNU159682 as taught by the ‘837 patent by utilizing an ethylenediamine modified PNU159682 for reaction with maleimide-PEG4-val-cit-PAB-PNP would result in the obvious variant of maleimide-PEG4-Val-Cit-PAB-EDA-PNU159682, as taught by ’985 and Cazzamalli.
Applicant argues that claims 1-57 of U.S. Patent No. 12,324,837 B2 in view of WO 2018/237335 fails to recite claimed compounds and WO 2018/237335 does not remedy this deficiency.
RESPONSE
Applicant’s arguments have been fully considered but are found non-persuasive essentially for the reasons of record and as further described supra.
In response to Applicant’s arguments that claims 1-57 of U.S. Patent No. 12,324,837 B2 fails to teach the claimed compounds of the instant application, the compounds of the ‘837 patent are an obvious variation of the instantly claimed invention. Furthermore, due to amendments of the claims of the instant application, the difference between the compounds of the ‘837 patent was the use of N,N’-dimethylethylenediamine rather than ethylenediamine of the instantly claimed invention which in this instance was taught by ’985 and Cazzamalli as discussed supra. Applicant has asked that the nonstatutory double patenting rejections be withdrawn; however, until Applicant has amended the claims of the instant application to provide patentable distinctiveness or filed a Terminal Disclaimer the nonstatutory double patenting rejections are maintained.
Claims 45-52 and 57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 115-132 of co-pending Application No. 18/257436; herein referred to as the “reference application.” Although the claims at issue are not identical, they are not patentably distinct from each other because the ROR1 specific target-binding molecule-drug conjugate of claim 129 of the reference application anticipates the target-binding molecule-drug conjugate of the instant application. Specifically, both target-binding molecule-drug conjugates comprise a specific antigen binding protein and a maleimide-spacer/linker-PNU159682 cytotoxin.
The co-pending claims of the reference application recite:
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The ROR1-specific antigen bind molecule of claim 115, wherein the ROR1-specific antigen binding molecule comprises the amino acid sequence selected from the group consisting of: SEQ ID NOs: 50-76 or a functional variant having CDR1, HV2, HV4, and CDR[[2]]3 sequences according to any thereof and having FW1, FW2, FW3a, FW3b, FW4 sequences having a combined sequence identity of at least 45% to the combine sequences of any thereof (i.e., claim 117); or wherein the ROR1 specific antigen binding molecule does not bind ROR2, binds to both hROR1 and mROR1, binds to deglycosylated ROR1, is humanized, is de-immunized, is conjugated to a detectable label, dye toxin, drug, etc., selectively interacts with ROR protein with an affinity constant of approximately 0.01 to 50 nM, etc., and/or is capable of mediating killing of ROR1 expressing tumor cells, etc. (i.e., claim 118).
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In this instance, because the target-binding molecule-drug conjugate of the reference application comprises a specific antigen binding protein, which in this instance binds ROR1 and not ROR2, there is no clear difference in the scope between the products of the instant and reference applications. In response, it is suggested that applicant either file a terminal disclaimer or amend the claims such that a clear and unmistakable line of separation exists between the products claimed in the instant application and those of the reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant argues that claims 115-132 of co-pending Application No. 18/257436 does not claim the earliest priority.
RESPONSE
Applicant’s arguments have been fully considered but are found non-persuasive essentially for the reasons of record and as further described supra.
Applicant has asked that the provisional nonstatutory double patenting rejections be withdrawn. Until Applicant has resolved all outstanding rejections and has amended the claims of the instant or co-pending application to provide patentable distinctiveness the provisional nonstatutory double patenting rejections are maintained.
Claims 45-57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 and 33-66 of co-pending Application No. 19/230346; herein referred to as the “reference application” in view of US 2018/0360985 (Zhu, et. al, 20DEC2018), herein referred to as “’985” and Cazzamalli, et al., (ACS Omega, 2018, 3, 14726-14731), herein referred to as “Cazzamalli.”
The co-pending claims of the reference application recite: A ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (II), wherein FW1 is a FW region, CDR1 is a CDR sequence,…X and Y are optional amino acid sequences, wherein the specific antigen binding molecule is conjugated to a second moiety (i.e., claim 50). The specific antigen binding molecule of claim 50, wherein the conjugation is via a cysteine residue in the amino acid sequence of the specific antigen binding molecule; or wherein the conjugation is via a thiol, aminooxy, or hydrazinyl moiety incorporated at the N- or C-terminus of the amino acid sequence of the specific antigen binding molecule; or wherein the second moiety is selected from the group comprising a detectable label, dye, toxin, drug, pro-drug, radionuclide, or biologically active molecule; or wherein the second moiety is at least one toxin selected from the group consisting of maytansinoids,…anthracycline, PNU-derived anthracyclines,…and pyridinobenzodiazepines; or wherein the specific antigen binding molecule is a ROR1 binding molecule (i.e., claims 52-53 and 55-57). The specific antigen binding molecule according to claim 57, wherein the ROR1-specific antigen binding molecule does not bind to ROR2; or wherein the ROR1 specific antigen binding molecule binds to both human ROR1 and murine ROR1; or wherein the ROR1 specific antigen binding molecule binds to deglycosylated ROR1; or wherein the ROR1 specific antigen binding molecule does not bind to a linear peptide sequence selected from SEQ ID NOs: 34-37; or wherein the FW1 is 20 to 28 amino acids, CDR1 is a CDR sequence selected from SEQ ID NO: 1, etc.,…or a functional variant thereof with at least 45% sequence identity thereto; or wherein FW1 is selected from SEQ ID NOs: 19-24, FW2 is selected from SEQ ID NOs: 25-26, FW3a is selected from SEQ ID NO: 27-28, FW3b is selected from SEQ ID NO: 29-31, and FW4 is selected from SEQ ID NO: 32-33 or functional variants thereof with sequence identity of at least 45%; or wherein the ROR1 specific antigen binding molecule comprises an amino acid sequence selected from SEQ ID NOs:39-49 (i.e., SEQ ID NO: 45 is 100% query match to SEQ ID NO: 45 of the instant application, OA.APPENDIX); or wherein the binding molecule is humanized; or wherein the binding molecule is de-immunized (i.e., claims 58-66, respectively).
In this instance, because claim 50 of the reference application is silent on the linker between the maleimide and the PNU-derived anthracycline, the specification was consulted to determine the scope of the structures claimed. Per the specification of the reference application the mal-linker-drug encompasses mal-PEG4-val-cit-PAB-DMEDA-PNU159682, wherein DMEDA is N,N’-dimethylethylenediamine (i.e., methyl groups on each amine, rather than hydrogens):
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(Fig 32).
However, they do not claim: the ethylenediamine between the PABC and drug.
Nevertheless, ‘985 teaches antibody drug conjugates, wherein the drug is selected from D1, D2, etc., and combinations thereof. The structure of D2 is:
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. In this instance the PNU derivative is modified with an ethylenediamine for reaction with the remainder of the linker of maleimide-PEG4-val-cit-PAB-PNP as synthesized in Cazzamalli:
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(section 4.2.2).
It would have been obvious to artisans to modify the issued products of an anti-ROR1 VNAR ADC utilizing thiol conjugation to the N- or C-terminus of the binding molecule and a PNU anthracycline derivative (i.e., maleimide-PEG4-Val-Cit-PAB-DMEDA-PNU159682 as claimed by the reference application to exchange the DMEDA-PNU159682 for EDA-PNU159682 derivative, as taught by ’985 and Cazzamalli. This is because both ethylenediamine (EDA) and N,N’-dimethylethylenediamine are frequently used as viable linker flanks to the self-immolative PABC because in combination they facilitate cyclization and payload (i.e., drug) release. One would have been motivated to do so, given the direction by the reference application that the anti-ROR1 VNAR could be linked to generally any PNU anthracycline derivative via a thiol reactive moiety (i.e., maleimide) with no limitations on the linker and furthermore, upon consultation of the specification to determine the scope of the claimed ADC of the reference application, the maleimide-PEG4-Val-Cit-PAB-DMEDA-PNU159682 structure is found to be an obvious variant of maleimide-PEG4-Val-Cit-PAB-EDA-PNU159682 as disclosed by ’985 and Cazzamalli. There would have been a reasonable expectation of success, given the knowledge that by modifying the anti-ROR1 VNAR ADC, wherein the PNU anthracycline derivative drug is conjugated to a thiol at the N- or C-terminus or has the structure of maleimide-PEG4-Val-Cit-PAB-DMEDA-PNU159682 as taught by the reference application by utilizing an ethylenediamine modified PNU159682 for reaction with maleimide-PEG4-val-cit-PAB-PNP would result in the obvious variant of maleimide-PEG4-Val-Cit-PAB-EDA-PNU159682, as taught by ’985 and Cazzamalli.
Applicant argues that claims 1-27 and 33-66 of co-pending Application No. 19/230346 in view of WO 2018/237335 fails to recite claimed compounds and WO 2018/237335 does not remedy this deficiency.
RESPONSE
Applicant’s arguments have been fully considered but are found non-persuasive essentially for the reasons of record and as further described supra.
In response to Applicant’s arguments that claims 1-27 and 33-66 of co-pending Application No. 19/230346 fails to teach the claimed compounds of the instant application, the compounds of the reference application are an obvious variation of the instantly claimed invention. Furthermore, due to amendments of the claims of the instant application, the difference between the compounds of the reference application was the use of N,N’-dimethylethylenediamine rather than ethylenediamine in the instantly claimed invention which in this instance was taught by ’985 and Cazzamalli as discussed supra. Applicant has asked that the provisional nonstatutory double patenting rejections be withdrawn. Until Applicant has resolved all outstanding rejections and has amended the claims of the instant or co-pending application to provide patentable distinctiveness the provisional nonstatutory double patenting rejections are maintained.
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.
Applicant’s claim amendments received as part of the 13FEB2026 response have necessitated the following new grounds of rejection.
Claims 45-47, and 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0369406 (Lannutti, et al., 27DEC2018), herein referred to as “’406” and in view of US 2018/0360985 A1 (Zhu, et. al, 20DEC2018), herein referred to as “’985,” Cheng, et al., (Mol Cancer Ther, 2018, 17, 2665-2675), herein referred to as “Cheng,” and WO 2018/103739 A1 (XDCExplorer, Co. Ltd., et. al, 14JUN2018, included in IDS), herein referred to as “’739.”
‘406 teaches ROR1 immunoconjugates comprising an anti-ROR1 antibody and a drug moiety as well as pharmaceutical formulations thereof:
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, wherein Ab is a ROR1 antibody and D is a drug (i.e., PNU-159682) (see entire document, specifically see ¶0007, ¶0186, ¶0014, and ¶0021).
However, they do not teach: the use of PEG4 or the use of EDA between the PABC and PNU-159682, or wherein the specific antigen binding protein is trastuzumab.
Nevertheless, ‘985 teaches ADCs, wherein the drug comprises anthracycline derivatives of structure D2:
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, which is equivalent to the EDA-PNU-159682 derivative of the instant application and further comprises linkers and/or spacers (i.e., PEG, etc.) and a conjugation moiety for attachment to an antibody (¶0015-0017 and ¶0031).
Additionally, Cheng teaches that the length of the PEG spacer group between the maleimide and the cleavable linker did not affect potency of the ADC, therefore no unexpected outcomes would result between the use of a PEG4 or PEG8 spacer (p 2670, col 2, ¶1).
Furthermore, ‘739 teaches that the antibody is Herceptin® (i.e., brand name of trastuzumab) and the pharmaceutical compositions include pharmaceutically acceptable excipients (summary of the invention section). ‘739 further teaches that typically, the antibody choice is dependent on the particular disease, which has a significant impact on the safety and efficacy of the ADC and the HER2 ADC invention is able to effectively treat HER2+ breast cancer cells.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the maleimide-PEG8-val-cit-PAB-PNU-159682 derivative taught by ‘406 by utilizing PEG4 instead of PEG8, EDA spacer between the PAB and PNU derivative, and a HER2 antibody as taught by ‘985, Cheng, and ‘739. One would have been motivated to use an EDA linker to flank the PABC moiety to facilitate cyclization and payload (i.e., drug) delivery, and to use a PEG4 linker because there is no significant difference in potency between a PEG4 and PEG8 linker, and to use trastuzumab instead of an anti-ROR1 antibody, because it is a well-known anti-HER2 antibody for treating HER2+ cancer. There would have been a reasonable expectation of success, given the knowledge that the maleimide-PEG8-val-cit-PABC-PNU159682 conjugate of ‘406 could be easily modified with an alternate PEG4 and the addition of a known EDA linker between the PABC and PNU derivative as taught by ‘985 and Cheng. There would have been a reasonable expectation of success for using Herceptin® (i.e., trastuzumab, anti-HER2 antibody), given the knowledge that the maleimide conjugation of the linker/spacer-EDA PNU159682 moiety to Herceptin® resulted in an effective HER2-targeted ADC therapeutic.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Conclusion
Claims 45-59 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. HOPKINS whose telephone number is (703)756-4666. The examiner can normally be reached Mon-Thurs 6:00 AM to 4:00 PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571)272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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