Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 82-101 are pending.
Claims 84 and 96-99 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 82-83 and 85-95, drawn to a drug conjugate that read on (A) ADC-1 having the following structure
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in claim 94, (B) D is P2 having the following structure
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, which is the second compound in claim 87, (C) -L-D having the following structure
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in claim 88 and (D) Ab-L-D having the following structure in claim 89, are being acted upon in this Office Action.
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Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
Objection and Rejection Withdrawn
The objection to claims 86, 90, 92 and 93 is withdrawn in view of the claim amendment.
The rejection of claim 82 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in view of claim amendment.
Claim objection
Claim 88 is objected to because of the following informality: duplicate structure
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on p 9 (elected P2) should be deleted.
Claim 89 is objected to because of the following informality: duplicate structure
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on p. 14 should be deleted.
Claim 94 is objected to because of the following informality: duplicate structure
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, which is the same as ADC-1, should be deleted. Further, the brackets in structures ADC-1, ADC-4, ADC-6, ADC-9, ADC-10, ADC-11, ADC-12, and ADC-18 are inconsistent with the brackets in structures ADC-5, ADC-16, ADC-17, ADC-21, ADC-22, ADC-25, ADC-26, ADC-27, ADC-28, ADC-29, ADC-30 and ADC-31. Correction is required.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 82-83 and 85-95 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other 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 applicant was in possession of the claimed genus.” (see MPEP 2163).
The claims encompass any drug conjugate having a structure represented by formula (I):
Ab-(L-D)p (I) or a pharmaceutically acceptable salt thereof, wherein the Ab is an anti-HER2 antibody or an antigen binding fragment thereof, comprising LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3; wherein the HCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 1, the HCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 2, and the HCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 3; and the LCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 4, the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 5, and the LCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 6; the structure of the D is:
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The specification exemplifies:
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505
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However, neither the specification nor the art teaches the broad genus of any drug conjugate comprising any fragment of 1, 2, 3, 4 or 5 CDRs of trastuzumab (claim 82) or any fragment of heavy chain variable region without the light chain variable region (claims 100-101) conjugated to any compound via linker comprises Mc-Val-Cit-PAB having the structure
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still maintains antigen binding to HER2 for treating any cancer or autoimmune disease.
The phrase “an amino acid sequence” in claims 82, 100 and 101 can be full-length as well as any fragment thereof.
Neither the art nor the specification teaches anti-HER2 antibody comprises any fragment of HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, and LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5 and LCDR3 of SEQ ID NO: 6 (claim 82) or any fragment of heavy chain variable region of SEQ ID NO: 7 and light chain variable fragment of SEQ ID NO: 8 (claim 100) or any fragment of heavy chain of SEQ ID NO: 9 and any light chain fragment of SEQ ID NO: 10 (claim 101) still maintains antigen binding.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target. 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. It is expected that all of the heavy and light chain CDRS (all six CDRs) in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. The specification provides no working examples showing that fewer than all six CDRs of the antibody or any fragment of heavy chain variable region and any fragment of light chain variable region or any fragment of heavy chain and any fragment of light chain of the antibody are required for binding to HER2 encompassed by the claimed conjugate. It is unlikely that an antibody as defined by claim 1, which may contain less the full complement of six CDRs from the heavy and light chain variable regions have the require binding function.
Chiu et al (of record, Antibodies 8: 55-80, 2019; PTO 892) teaches 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 immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (see p. 4, in particular). As such, any drug conjugate comprising just fragment of heavy and light chain CDRs 1-3 from trastuzumab or any fragment of heavy chain variable region and fragment of light chain variable region or any fragment of heavy chain and light chain cannot bind HER2, much less for use to target the drug to cell expressing HER2 to inhibit cell proliferation in vitro or in vivo.
There are insufficient in vivo working examples. One of skill in the art would not immediately envision or recognize which drug conjugate is effective for treating any and all possible cancer and autoimmune disease.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, only an antibody drug conjugate having a structure represented by formula (I): Ab-(L-D)p, wherein the Ab is an anti-HER2 antibody trastuzumab or an antigen binding fragment thereof comprising a heavy chain CDRs 1-3 of SEQ ID NO: 1 to 3, respectively, and a light chain CDRs 1-3 of SEQ ID NO: 4-6, respectively, or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8 or a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10, wherein the L-D is
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and wherein the p is an integer from 1 to 4 for treating HER2 expressing cancer, (2) the antibody drug conjugate above having the structure of ADC-1, ADC-6 as shown in claim 94, and a pharmaceutical composition comprising the antibody drug conjugate above and a pharmaceutically acceptable carrier for treating HER2 expressing breast ductal carcinoma, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Applicants’ arguments filed July 22, 2026 have been fully considered but are not found persuasive.
Applicant has amended claim 82 to specify that the Ab is an anti-HER2 antibody or an antigen binding fragment, comprising LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3 and that the HCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 1, HCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 2, and HCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 3; and the LCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 4, LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 5, and LCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 6, and has amended claims 82-95 to delete "or the solvate, the racemic mixture, the enantiomer, the diastereomer or the tautomer thereof'.
Regarding conjugate salt, the claimed drug conjugates contain one or more ionizable functional groups capable of forming pharmaceutically acceptable salts. Formation of pharmaceutically acceptable acid-addition or base-addition salts of compounds containing ionizable groups is a routine and well-established practice in the art. A person of ordinary skill in the art would readily recognize suitable counterions and conventional methods for preparing such salts without undue experimentation. Furthermore, formation of a pharmaceutically acceptable salt changes only the ionic form of the disclosed conjugate and does not alter the underlying antibody, linker, or payload structure.
The amended claims are directed to a drug conjugate, in which
" the antibody (Ab) is an anti-HER2 antibody or an antigen binding fragment, which is
defined by the specific sequences of LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and
HCDR3;
" the linker (L) has a specifically defined structure:
" D (payload) has the following structure:
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In response, the amendment to claim 82 is acknowledged. The issue with respect to solvate, racemic mixture, enantiomer, diastereomer and tautomer is moot in view of the claim amendment.
The issue with respect to claims 82, 100 and 101 is “an amino acid sequence”. The phase “an amino acid sequence” encompasses full-length sequence as well as any fragment thereof.
Neither the art nor the specification teaches anti-HER2 antibody comprises any fragment of HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, and LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5 and LCDR3 of SEQ ID NO: 6 (claim 82) or any fragment of heavy chain variable region of SEQ ID NO: 7 and light chain variable fragment of SEQ ID NO: 8 (claim 100) or any fragment of heavy chain of SEQ ID NO: 9 and any light chain fragment of SEQ ID NO: 10 (claim 101) still maintains antigen binding.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target. 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. It is expected that all of the heavy and light chain CDRS (all six CDRs) in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. The specification provides no working examples showing that fewer than all six CDRs of the antibody or any fragment of heavy chain variable region and any fragment of light chain variable region or any fragment of heavy chain and any fragment of light chain of the antibody are required for binding to HER2 encompassed by the claimed conjugate. It is unlikely that an antibody as defined by claim 1, which may contain less the full complement of six CDRs from the heavy and light chain variable regions have the require binding function.
Chiu et al (of record, Antibodies 8: 55-80, 2019; PTO 892) teaches 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 immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (see p. 4, in particular). As such, any drug conjugate comprising just any fragment of heavy and light chain CDRs 1-3 from anti-HER2 antibody or antigen binding fragment thereof (claim 82) or any fragment of heavy chain variable region and fragment of light chain variable region (claim 100) or any fragment of heavy chain and light chain (claim 101) cannot bind HER2, much less for use to target the drug to cell expressing HER2 to inhibit cell proliferation in vitro or in vivo.
There are insufficient in vivo working examples. One of skill in the art would not immediately envision or recognize which drug conjugate is effective for treating any and all possible cancer and autoimmune disease.
For these reasons, the rejection is maintained.
Claims 82-83 and 85-95 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an antibody drug conjugate having a structure represented by formula (I): Ab-(L-D)p, wherein the Ab is an anti-HER2 antibody trastuzumab or an antigen binding fragment thereof comprising a heavy chain CDRs 1-3 of SEQ ID NO: 1 to 3, respectively, and a light chain CDRs 1-3 of SEQ ID NO: 4-6, respectively, or a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8 or a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10, wherein the L-D is
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and wherein the p is an integer from 1 to 4 for treating HER2 expressing cancer, (2) the antibody drug conjugate above having the structure of ADC-1 or ADC-6 as shown in claim 94, and a pharmaceutical composition comprising the antibody drug conjugate above and a pharmaceutically acceptable carrier for treating HER2 expressing breast ductal carcinoma, does not reasonably provide enablement for the claimed drug conjugate having a structure represented by formula I: Ab-(L-D)p or any acceptable salt thereof, in which the anti-HER2 antibody or antigen binding fragment thereof comprising a HCDR1 comprising any fragment of SEQ ID NO: 1, a HCDR2 comprising any fragment of SEQ ID NO: 2, a HCDR3 comprising any fragment of SEQ ID NO: 3, and a LCDR1 comprising any fragment of SEQ ID NO: 4, a LCDR2 comprising any fragment of SEQ ID NO: 5 and a LCDR3 comprising any fragment of SEQ ID NO: 6 (claim 82), or heavy chain variable region comprising any fragment of SEQ ID NO: 7 and light chain variable region comprising any fragment of SEQ ID NO: 8 (claim 100), or heavy chain comprising any fragment of SEQ ID NO: 9 and light chain comprising any fragment of SEQ ID NO: 10 (claim 101). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The claims encompass any drug conjugate having a structure represented by formula (I):
Ab-(L-D)p (I) or a pharmaceutically acceptable salt thereof, wherein the Ab is an anti-HER2 antibody or an antigen binding fragment thereof, comprising LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3; wherein the HCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 1, the HCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 2, and the HCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 3; and the LCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 4, the LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 5, and the LCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 6; the structure of the D is:
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The specification exemplifies:
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655
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480
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495
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390
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258
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600
769
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477
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365
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513
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Enablement is not commensurate in scope with the claims because the phrase “an amino acid sequence” encompasses full-length sequence as well as any fragment thereof.
One cannot extrapolate the disclosure of the specification to the enablement of the claims because the specification does not teaches anti-HER2 antibody comprises any fragment of HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, and LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5 and LCDR3 of SEQ ID NO: 6 (claim 82) or any fragment of heavy chain variable region of SEQ ID NO: 7 and light chain variable fragment of SEQ ID NO: 8 (claim 100) or any fragment of heavy chain of SEQ ID NO: 9 and any light chain fragment of SEQ ID NO: 10 (claim 101) still maintains antigen binding.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target. 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. It is expected that all of the heavy and light chain CDRS (all six CDRs) in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. The specification provides no working examples showing that fewer than all six CDRs of the antibody or any fragment of heavy chain variable region and light chain variable region or any fragment of heavy chain and light chain of the antibody still maintain binding to HER2 encompassed by the claimed conjugate. It is unlikely that an antibody as defined by claims 82, 100 and 101 have the require binding function.
Chiu et al (of record, Antibodies 8: 55-80, 2019; PTO 892) teaches 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 immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (see p. 4, in particular). As such, any drug conjugate comprising any fragment of heavy and light chain CDRs 1-3 from anti-HER2 antibody or any fragment of heavy chain variable region and fragment of light chain variable region or any fragment of heavy chain and light chain cannot bind HER2, much less for use to target the drug to cell expressing HER2 to inhibit cell proliferation in vitro or in vivo.
There are insufficient in vivo working examples. It is unpredictable which fragment of anti-HER2 antibody conjugated to any drug as set forth in claims is effective for treating any and all possible cancer and autoimmune disease.
As such, it would require undue experimentation of one skilled in the art to practice the claimed invention commensurate in scope with the claims. See page 1338, footnote 7 of Ex parte Aggarwal, 23 USPQ2d 1334 (PTO Bd. Pat App. & Inter. 1992).
Applicants’ arguments filed July 22, 2026 have been fully considered but are not found persuasive.
The Examiner's rejection is focused on antibody and salt or solvate or racemic mixture or enantiomer or diastereomer or tautomer. In response, Applicant has amended claim 82 to specify that the Ab is an anti-HER2 antibody or an antigen binding fragment, comprising LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3 and that the HCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 1, HCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 2, and HCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 3; and the LCDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 4, LCDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 5, and LCDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 6, and has amended claims 82-95 to delete "or the solvate, the racemic mixture, the enantiomer, the diastereomer or the tautomer thereof'.
With regard to conjugate salt, the Examiner has not identified any aspect of preparing the claimed salts that would require undue experimentation. Formation of pharmaceutically acceptable salts from compounds containing ionizable functional groups is a routine operation well within the ordinary skill in the art. Furthermore, formation of a pharmaceutically acceptable salt changes only the ionic form of the disclosed conjugate and does not alter the underlying antibody, linker, or payload structure. Accordingly, the specification enables a person of ordinary skill in the art to make and use such salts without undue experimentation.
Clear depictions of claimed conjugates by structural chemical formulas are shown
throughout the specification and claims. See, e.g., originally-filed application, pages 29-76. The Anti-HER2 antibodies are described in detail on page 62 of the specification. The linker recited in claim 82 is described on page 46. Payloads are described in Example 2. Preparation of Linker- Payloads (LPs) is described in Example 3. Preparation of ADCs is described in Example 4, and tested in Examples 5-10. Specifically, 35 compounds falling with the scope of the payload (LP) recited in claim 82 are prepared in Example 2. 31 ADCs (ADC-1 to ADC-31) falling within the scope of claim 82 are prepared and tested in the Examples.
Enablement requires that the specification describe how to make and use the invention, which this specification does. In this specification, conjugates are depicted, exemplified, and tested. Based on the teachings of the specification and the knowledge in the art, one of ordinary skill could have made the entire scope of the claimed drug conjugate without undue experimentation.
In response, the amendment to claim 82 is acknowledged. The issue with respect to solvate, racemic mixture, enantiomer, diastereomer and tautomer is moot in view of the claim amendment.
The issue with respect to claims 82, 100 and 101 is “an amino acid sequence”. The phase “an amino acid sequence” encompasses full-length sequence as well as any fragment thereof. Enablement is not commensurate in scope with the claims because the phrase “an amino acid sequence” encompasses full-length sequence as well as any fragment thereof.
Neither the art nor the specification teaches anti-HER2 antibody comprises any fragment of HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, and LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5 and LCDR3 of SEQ ID NO: 6 (claim 82) or any fragment of heavy chain variable region of SEQ ID NO: 7 and light chain variable fragment of SEQ ID NO: 8 (claim 100) or any fragment of heavy chain of SEQ ID NO: 9 and any light chain fragment of SEQ ID NO: 10 (claim 101) still maintains antigen binding.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target. 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. It is expected that all of the heavy and light chain CDRS (all six CDRs) in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. The specification provides no working examples showing that fewer than all six CDRs of the antibody or any fragment of heavy chain variable region and any fragment of light chain variable region or any fragment of heavy chain and any fragment of light chain of the antibody are required for binding to HER2 encompassed by the claimed conjugate. It is unlikely that an antibody as defined by claim 1, which may contain less the full complement of six CDRs from the heavy and light chain variable regions have the require binding function.
Chiu et al (of record, Antibodies 8: 55-80, 2019; PTO 892) teaches 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 immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (see p. 4, in particular). As such, any drug conjugate comprising just any fragment of heavy and light chain CDRs 1-3 from anti-HER2 antibody or antigen binding fragment thereof (claim 82) or any fragment of heavy chain variable region and fragment of light chain variable region (claim 100) or any fragment of heavy chain and light chain (claim 101) cannot bind HER2, much less for use to target the drug to cell expressing HER2 to inhibit cell proliferation in vitro or in vivo.
There are insufficient in vivo working examples. One of skill in the art would not predict which drug conjugate is effective in vivo for treating any and all possible cancer and autoimmune disease.
In response to the argument that the conjugates are depicted, exemplified, and tested, the specification tested only trastuzumab conjugated to compound 1 (ADC-6) and compound 2 (ADC-18), see Examples 4-7, 9. But the claims are drawn to trastuzumab conjugated to compounds P3 to p35. It is not clear conjugates comprising compound P3 to p35 have the same activities for treating any and all possible cancer or autoimmune disease. There are insufficient in vivo working examples. It is unpredictable which conjugate is effective for treating cancers that do not express HER2, much less any and all possible autoimmune disease.
For these reasons, the rejection is maintained.
Conclusion
No claim is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
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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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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