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 26-32 are pending and currently under consideration.
Claim 26 is the independent claim.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831 (a) requires that patent applications which contain disclosures of
nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR
1.831 (b) must contain a "Sequence Listing XML", 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 1.831-.835. This "Sequence Listing XML" part of the disclosure may be submitted:
In accordance with 37 CFR 1.831 (a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO's patent electronic filing system (Patent Center) (see Section 1.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/patentsapplication- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
In accordance with 37 CFR 1.831 (a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE
AS FOLLOWS:
As is most readily apparent in Table C (Sequences) spanning pages 88-96 of the specification filed 7/5/2023, applicant has assigned a SEQ ID number to a tripeptide heavy chain HVR-H2 sequence (PD1-0103) and a tripeptide light chain HVR-L2 sequence (PD1-0103). However, under ST.26, it is impermissible for a SEQ ID number to be used to refer to such a short amino acid sequence. 37 CFR 831 is reproduced
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242
779
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below for applicant's convenience (emphasis added by the examiner).
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It is noted that the XML sequence listing file contains no data for this tripeptide, as the
sequence identified by SEQ ID number in the table is "blank" in the XML file (i.e. no
data). While it is proper that such short three amino acid peptide sequences do not
appear in the sequence listing, applicant giving such sequences SEQ ID numbers in the
specification sets up a situation wherein the application is logically inconsistent.
Specifically, if an artisan looks at the sequence listing to determine what is SEQ ID
N0:2 and SEQ ID NO:5 they will find it is nothing at all, whereas if they look for the same information on page 88 they find it to be the tripeptides "GGR" and “RSS”, respectively. The same term cannot have two different meanings, and since as per 37 CFR1 .831 as quoted above it is impermissible for amino acid sequences shorter than 4 specifically defined residues to be defined via SEQ ID number it is the specification which is in error. As such, applicant must remove all reference to said tripeptides by way of SEQ ID number. For example, instant claim 1 must not recite "SEQ ID NO: 2" and “SEQ ID NO:5” and must instead spell out the tripeptide "GGR" and “RSS”, respectively. Similarly the table spanning pages 88-96 also cannot assign a SEQ ID number for the tripeptide heavy chain HVR-H2 and light chain HVR-L2 sequences. Note that such changes must be made at all occurrences everywhere in the specification, including figures, drawings, and text. Note also that this issue of inappropriately assigning SEQ ID numbers to short sequences may apply to additional sequences other than "SEQ ID NO: 2" and “SEQ ID NO:5” and that no attempt has been made by the examiner to find and catalog all such errors throughout the 111 page specification. Appropriate correction is required.
Information Disclosure Statement
The references in the IDS filed on 7/5/2023 and 9/11/2024 have been considered by the examiner.
Claim Objections
Claim 29 is objected to because of the following informalities:
Claim 29 recites, “The method of claim 26, the anti-CD20/anti-CD3 bispecific antibody is glofitamab.”, which should recite, “ “The method of claim 26, wherein the anti-CD20/anti-CD3 bispecific antibody is glofitamab.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Enablement
Claims 26-32 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: a method of treating a CD20 expressing cancer in a subject wherein the CD20 expressing cancer refers to lymphomas (preferably B-Cell Non-Hodgkin's lymphomas (NHL)) and lymphocytic leukemias and B cell proliferative disorders, the specification does not reasonably provide enablement for a method of treating an CD20 expressing cancer.
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 or use the invention commensurate in scope with the claims. The specification does not enable one skilled in the art to practice the invention without undue amount of experimentation.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The specification (pages 40-41), describes a definition of a “CD20 expressing cancer” which recites “refers to all cancers in which the cancer cells show an expression of the CD20 antigen. Preferably CD20 expressing cancer are used herein refers to lymphomas (preferably B-Cell Non-Hodgkin’s lymphomas (NHL)) and lymphocytic leukemias.”. Additionally, the specification (page 41) provides another definition for "B cell proliferative disorder" is meant a disease wherein the number of B cells in a patient is increased as compared to the number of B cells in a healthy subject, and particularly wherein the increase in the number of B cells is the cause or hallmark of the disease. A "CD20-positive B cell proliferative disorder" is a B cell proliferative disorder wherein B-cells, particularly malignant B-cells (in addition to normal B-cells), express CD20. Exemplary B cell proliferation disorders include Non-Hodgkin lymphoma (NHL), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle-cell lymphoma (MCL), marginal zone lymphoma (MZL), as well as some types of Multiple myeloma (MM) and Hodgkin lymphoma (HL).” However, there is no definition of the minimum and/or maximum threshold expression needed for a cancer to be characterized as a CD20 expressing cancer.
Additionally, the specification (page 106, example 3) describes the effect of PD-1/LAG-3 bispecific antibodies in combination with CD20 CD3 TCB on ARH77 cell lines (B-cell lymphoblastoid cell line) in comparison to PD-1 blocking antibodies in combination with CD20-TCB therapy and the PD-1/LAG-3 BsAb was more potent and efficacious than PD-1 blocking antibodies in increasing Granzyme B secreted in CD4 T cells making it a more suitable partner for CD20-TCB. Examples 4-6 (pages 106-111) describes the potent anti-tumor effect of the combination of PD1/LAG3 BsAb and CD20 CD3 TCB in HSC-NSG mice engrafted with human diffuse large B cell lymphoma. However, there are no other examples of other CD20 expressing cancers.
The breadth of the instant claims encompass any CD20 expressing cancers.
The art of Pavlasova et al (PTO-892; Reference W) teaches that CD20 is a general B-cell marker for the majority of B cells; however, there is a subset of CD20+ T cells with immune regulatory and pro-inflammatory activity (Pavlasova; page 1497, left column, paragraph 2). Pavlasova teaches the level of CD20 expression is extremely variable depending on the specific neoplasm, with the lowest CD20 expression usually being observed in patients with CLL, and the highest CD20 cell-surface expression on DLBCL and hairy cell lymphoma (Pavlasova; page 1497, left column, paragraph 2). CD20 is not only heterogenous among patients with the same malignancy but also within the intraclonal cell subpopulations in an individual patient (Pavlasova; page 1497, left column, paragraph 2).
Nelson (PTO-892; Reference V) teaches that B cells are commonly activated in human cancer patients and the activated B cells (i.e. tumor-infiltrating CD20+ B cells) are present in breast cancer, ovarian cancer, cervical cancer, germ cell tumors, colorectal cancer, non-small cell lung cancer, etc. (Nelson; page 4978-4978, right column, B cells in cancer section).
Additionally, the art of Kyvsgaard et al (PTO-892; Reference U) also teaches that patients with B-cell neoplasms with reduced CD20 expression had an inferior response rates compared to patients with strong CD20 expression when treated with CD20xCD3 bispecific antibodies (Kyvsgaard; page 3, left column, paragraph 4).
The prior art does not appear to provide any evidence as to treatment of the fullest scope of instant claim 1 of any as such, not all cancers and/or individual patients express CD20 uniformly, CD20 can be expressed in a tumor due to tumor infiltrating lymphocytes, and cancers with different CD20 expression levels have different response rates to CD20xCD3 bispecific antibodies.
Furthermore, claims 26-32 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: a method of treating a CD20 expressing cancer in a subject comprising administering to the subject an effective amount of an anti-CD20/anti-CD3 antibody wherein the antibody is glofitamab wherein the anti-CD20/anti-CD3 antibody of comprises a first CD3 antigen binding arm comprising SEQ ID NO: 47 and 48 which encompasses 6 CDRs of SEQ ID NOs: 41-46 and a second CD20 antigen binding arm comprising SEQ ID NOs:55 and 56 which encompass 6 CDRs of SEQ ID NOs: 49-54 and an effective amount of an anti-PD-1/anti-LAG3 bispecific antibody wherein the first PD-1 antigen binding arm comprising SEQ ID NOs:9 and 10, which encompasses 6 CDRs of SEQ ID NOs:1-6 wherein the second LAG3 antigen binding arm comprising SEQ ID NOs:17 and 18 which encompasses 6 CDRs of SEQ ID NOs:11-16, and 6 CDRs of SEQ ID NOs:19-24, the specification does not reasonably provide enablement for a method of treating a CD20 expressing cancer in a subject comprising administering an effective amount of an anti-CD20/anti-CD3 antibody and an effective amount of an anti-PD-1/anti-LAG3 bispecific antibody.
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 or use the invention commensurate in scope with the claims. The specification does not enable one skilled in the art to practice the invention without undue amount of experimentation.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The specification discloses the anti-CD20/anti-CD3 antibody comprising the first antigen binding domain comprising a heavy chain variable region (VHCD3) and a light chain variable region (VLCD3) which comprise SEQ ID NO: 47 and 48 which encompasses 6 CDRs of SEQ ID NOs: 41-46 and a second antigen binding domain comprising a heavy chain variable region (VHCD20) and a light chain variable region (VLCD20) which comprise SEQ ID NOs:55 and 56 which encompass 6 CDRs of SEQ ID NOs: 49-54. The specification additionally describes wherein the anti-CD20/anti-CD3 antibody is glofitamab, a novel T-cell-engaging bispecific full-length antibody with a 2:1 molecular configuration for bivalent binding to CD20 on B cells and monovalent binding to CD3, particularly the CD2 epsilon chain, on T cells. However, the specification is not enabled for making and using an “anti-CD20/anti-CD3 antibody”. The specification has not adequately disclosed the genus of this molecule which can be made and used commensurate in scope with the specification for use in a method of treating CD20 expressing cancer in combination with an anti-PD-1/anti-LAG3 bispecific antibody.
The specification discloses the anti-PD-1/anti-LAG3 bispecific antibody comprising the anti-PD-1 antigen binding arm comprising SEQ ID NOs:9 and 10 which comprise the 6 CDRs of SEQ ID NOs: 1-6 for use in the claimed invention. The specification also discloses the anti-PD-1/anti-LAG3 bispecific antibody comprising the anti-LAG3 antigen binding arm comprising SEQ ID NOs: 17 and 18 which comprise 6 CDRs of SEQ ID NOs: 11-16 and 6 CDRS of SEQ ID NOs: 19-24 for use in the claimed invention. The specification is not enabled for making and using “an anti-PD-1/anti-LAG3 bispecific antibody”. The specification has not adequately disclosed the genus of this molecule which can be made and used commensurate in scope with the specification for use in a method of treating CD20 expressing cancer in combination with an anti-CD20/anti-CD3 antibody.
The breadth of the instant claims encompass antibodies with fewer than all six CDRs found in the heavy plus light chain binding region. The specification does not adequately disclose how the skilled artisan would make and use the various antibodies recited in the instant claims.
It is well established in the art that it is highly unpredictable which changes in amino acid sequence can be made in complementarity determining regions (CDRs) of a parental antibody such that the derived antibody retains the binding specificity and affinity of the parent antibody.
The art of Mariuzza et al. (PT0-892; Reference X) reviews the structural basis of antigen-antibody recognition and teaches that a naturally occurring antibody comprises light and heavy chains. The antigen-combining site of an antibody is a three-dimensional structure, which fully comprises six "complementarity-determining regions" (CDRs), three each from the light and heavy chains. The amino acid sequences of the CD Rs are hypervariable, as the amino acid residues contained within the CDRs determine much of antibody's antigen-binding specificity. Of the amino acid residues of the antibody contacting the antigen, six are within the light chain, nine are within the heavy chain, and two are within the constant or nearly constant "framework" regions (In particular, whole document). As such, one of skill in the art would not be able to make and use the genus of recited antibodies which would retain antigen binding function, because it is the 6 CDRs together which determine the antibody's antigen-binding specificity, but the specification sets forth that amino acids in CDRs can be varied from the parental antibody without identifying which CDR residues of the particularly disclosed antibodies that can be altered to retain antigen-binding function.
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 epitope. The amino acid sequences and conformations of each of the heavy and light chain CD Rs 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 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. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function.
Rudikoff et al. (PT0-892; page 2, Reference U) teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (In particular, page 1979, whole document). Rader et al. (PT0-892; page 2, Reference V) teaches in vitro selection and evolution of antibodies derived from phage display libraries by pairing either heavy or light chain of the rodent antibody with human polypeptide library for humanization is unpredictable, and certain antibodies cannot be humanized using this approach; and in addition, antibodies consisting of the same heavy chain paired with light chains that differ in light chain CDR3 and elsewhere in VL can obtain undesired feature of binding different epitopes of the same antigen (In particular, discussion on pages 8914-8915, whole document). Accordingly, since it is known in the art that antibodies can comprise the same CDR3 amino acid sequences but not share antigen-binding specificity, it is apparent that one of skill in the art could not be able to make and use the genus of recited antibodies which would retain binding specificity and antagonist function. For these reasons, one of skill in the art would not recognize that the specification is not enabled for the use of the genus of the recited antibodies.
The specification provides insufficient direction or guidance regarding how to produce antibodies as broadly defined by the claims other than the anti-CD20/anti-CD3 antibody of SEQ ID NO: 47 and 48 which encompasses 6 CDRs of SEQ ID NOs: 41-46 and SEQ ID NOs:55 and 56 which encompass 6 CDRs of SEQ ID NOs: 49-54; and the anti-PD-1/anti-LAG3 antibody of SEQ ID NOs:9 and 10 which comprise the 6 CDRs of SEQ ID NOs: 1-6 and SEQ ID NOs: 17 and 18 which comprise 6 CDRs of SEQ ID NOs: 11-16 and 6 CDRs of SEQ ID NOs:19-24. One of ordinary skill in the art would be required to practice undue experimentation to practice the invention commensurate in scope with the claimed.
In view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trials and errors to make and use the claimed antibodies with less than six CDRs.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
Written Description
Claims 26-32 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.
Claims 26-32 encompasses a broad genus of CD20 expressing cancers. The claims encompass all CD20 expressing cancers.
The specification (page 40-41) describes a CD20 expressing cancer to refer to all cancers in which the cancer cells show an expression of the CD20 antigen which preferably refers to lymphomas (preferably B-Cell Non-Hodgkin’s lymphomas), lymphocytic leukemia, and B-cell proliferative disorders wherein malignant B cels express CD20. The specification (page 106, example 3) does provide examples of combination PD-1/LAG3 bispeciifc antibody and CD20 CD3 TCB on ARH77 cell lines (B-cell lymphoblastoid cell lines) in comparison to PD-1 antibody in combination with CD20 TCB therapy and the PD-1/LAG3 BsAb was more potent and efficacious then PD-1 antibody in increasing Granzyme B secreted in CD4 T cells making it a more suitable partner for CD20-TCB. Examples 4-6 (pages 106-111) describes the potent anti-tumor effect of the combination of PD1/LAG3 BsAb and CD20 CD3 TCB in HSC-NSG mice engrafted with human diffuse large B cell lymphoma. However, there are no other examples of other CD20 expressing cancers. The specification has not adequately described the exact definition of a CD20 expressing cancer or what expression level (high, medium, or low) qualifies a cancer as CD20 expressing.
However, there does not appear to be adequate written description in the specification as-filed of the essential definition and minimum expression of CD20 for a cancer to be characterized as a CD20 expressing cancer. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or U.S.C 112, ¶ 1 "Written Description" Requirement make clear that 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, reduction to drawings, or 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 genus.
Absent a limiting definition for the term “CD20 expressing cancer” the term opens up the claimed invention to encompass all CD20 expressing cancers (i.e. cancers with high, medium, and low expression of CD20). The art of Pavlasova et al (PTO-892; Reference W) teaches CD20 expression is extremely variable depending on the specific neoplasm, with the lowest CD20 cell-surface expression usually observed in patients with CLL, and the highest CD20 cell-surface expression on DLBCL and hairy cell lymphoma (Pavlasova; page 1497, left column, paragraph 2). CD20 is not only heterogenous among patients with the same malignancy but also within the intraclonal cell subpopulations in an individual patient (Pavlasova; page 1497, left column, paragraph 2). Furthermore, the art of Kyvsgaard et al (PTO-892; Reference U) also teaches that patients with B-cell neoplasms with reduced CD20 expression had an inferior response rates compared to patients with strong CD20 expression when treated with CD20xCD3 bispecific antibodies (Kyvsgaard; page 3, left column, paragraph 4).
Claims 26-32 do not meet the requirements of 35 U.S.C. 112(a) for written description as they are currently written. The examiner recommends narrowing the scope of “CD20 expressing cancer” in independent claim 26 a particular cancer subtype.
Additionally, Claims 26-32 encompass a broad genus of anti-CD20/anti-CD3 bispecific antibodies and PD-1/LAG3 bispecific antibodies. The claims encompass all variants of anti-CD20/anti-CD3 and PD-1/LAG3 bispecific antibodies.
The specification describes the anti-CD20/anti-CD3 antibody comprising heavy chain variable region (VHCD3) and a light chain variable region (VLCD3) which comprise SEQ ID NO: 47 and 48 which encompasses 6 CDRs of SEQ ID NOs: 41-46 and a second antigen binding domain comprising a heavy chain variable region (VHCD20) and a light chain variable region (VLCD20) which comprise SEQ ID NOs:55 and 56 which encompass 6 CDRs of SEQ ID NOs: 49-54 for use in the claimed invention. The specification additionally describes wherein the anti-CD20/anti-CD3 antibody is glofitamab for use in the claimed invention.
The specification discloses the anti-PD-1/anti-LAG3 bispecific antibody comprising the anti-PD-1 antigen binding arm comprising SEQ ID NOs:9 and 10 which comprise the 6 CDRs of SEQ ID NOs: 1-6 for use in the claimed invention. The specification also discloses the anti-PD-1/anti-LAG3 bispecific antibody comprising the anti-LAG3 antigen binding arm comprising SEQ ID NOs: 17 and 18 which comprise 6 CDRs of SEQ ID NOs: 11-16 and 6 CDRs of SEQ ID NOs:19-24 for use in the claimed invention.
The specification has not adequately described “an anti-CD20/anti-CD3 antibody” and “an anti-PD-1/anti-LAG3 bispecific antibody”. The specification has not adequately described the structure of the molecules with these functions. The specification also has not adequately described “a CD20 expressing cancer” or provide a sufficient number of representative examples of CD20 expressing cancers. Therefore, the skilled artisan cannot envision all the antibody and method possibilities recited in the instant claims.
Consequently, conception cannot be achieved until a representative description of the structural and functional properties of the claimed invention has occurred, regardless of the complexity or simplicity of the method.
As outlined in Amgen Inc. v. Sanofi, 598 U.S. 594 (2023), broad antibody genus claims must be supported either by a sufficient number of representative species or common structural features that define the genus. Disclosure of only one or a few antibody species is insufficient where the claim encompasses a large and structurally diverse genus.
The specification does not provide adequate written description of the claimed invention. The legal standard for sufficiency of a patent's (or a specification's) written description is whether that description "reasonably conveys to the artisan that the inventor had possession at that time of the ... claimed subject matter", Vas-Cath, Inc. V. Mahurkar, 19 U.S.P.Q.2d 1111 (Fed. Cir. 1991). In the instant case, the specification does not convey to the artisan that the applicant had possession at the time of invention of the claimed inventions.
The claims encompass antibodies with variants of the recited amino acid sequences. The claims recite variable region sequences containing amino acids not found in the antibodies that were actually produced in the examples in the specification which actually bind to the recited PD-1 sequences in claim 26 and LAG-3 sequences in claim 27. The claims recite combinations of CDRs wherein the combinations encompass antibodies other than the specific antibodies produced in the examples in the specification which actually bind the recited PD-1 in claim 26 and LAG3 sequences in claim 27. The claims recites an anti-CD20/anti-CD3 antibody and a second LAG3 antigen binding arm of the anti-PD-1/anti-LAG3 bispecific antibody without any structure.
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. MacCallum, et al. (PTO-892; Page 4, Reference U) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column). De Pascalis, et al. (PTO-892; Page 3, Reference X) demonstrates that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right column). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left column). Thus it is unpredictable as to what amino acids can be changed in the original intact antibodies disclosed in the specification wherein the antibodies would still function. Thus, the skilled artisan cannot envision the detailed structure of the encompassed invention and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation.
Adequate written description requires more than a mere statement that it is part of the invention and a reference to a potential method of isolating it. In the instant application, the amino acid sequence itself or isolated protein is required. See Fiers v. Revel, 25 USPQ 2d 160 I at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Lts., 18 USPQ2d 1016. In view of the aforementioned problems regarding description of the claimed invention, the specification does not provide an adequate written description of the invention claimed herein. See The Regents of the University of California v. Eli Lilly and Company, 43 USPQ2d 1398, 1404-7 (Fed. Cir. 1997). In University of California v. Eli Lilly and Co., 39 U.S.P.Q.2d 1225 (Fed. Cir. 1995) the inventors claimed a genus of DNA species encoding insulin in different vertebrates or mammals, but had only described a single species of cDNA which encoded rat insulin. The court held that only the nucleic acids species described in the specification (i.e. nucleic acids encoding rat insulin) met the description requirement and that the inventors were not entitled to a claim encompassing a genus of nucleic acids encoding insulin from other vertebrates, mammals or humans, id. at 1240. The Federal Circuit has held that if an inventor is "unable to envision the detailed constitution of a gene so as to distinguish it from other materials . . . conception has not been achieved until reduction to practice has occurred", Amgen, Inc. v. Chugai Pharmaceutical Co, Ltd., 18 U.S.P.Q.2d 016 (Fed. Cir. 1991). Attention is also directed to the decision of The Regents of the University of California v. Eli Lilly and Company (CAFC, July 1997) wherein is stated: "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, 222 USPQ 369, 372-373 (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. Thus, as we have previously held, a cDNA is not defined or described by the mere name "cDNA," even if accompanied by the name of the protein that it encodes, but requires a kind of specificity usually achieved by means of the recitation of the sequence of nucleotides that make up the cDNA." See Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606.
As such, there is insufficient written description of the required kind of structure identifying information about the corresponding makeup of the claimed antibodies to demonstrate possession.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
Priority
This application is a Continuation of PCT/EP2022/050040 effectively filed on 1/4/2022.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 21150425.3, filed on 1/6/2021.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 26-28 and 30-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/185043 A1 (PTO-892; Reference N; “Codarri Deak”) in view of US 2017/0174779 A1 (PTO-892; Reference A; “Varghese”) and Maruhashi et al (PTO-892; Page 2, Reference W; “Maruhashi”).
Claim 1 recites:
A method for treating a CD20 expressing cancer in a subject comprising administering to the subject an effective amount of an anti-CD20/anti-CD3 antibody and an effective amount of an anti-PD1/anti-LAG3 bispecific antibody, wherein the anti-PD1/antiLAG3 bispecific antibody comprises a first antigen binding domain that specifically binds to programmed cell death protein 1 (PD 1) and a second antigen binding domain that specifically binds to Lymphocyte activation gene-3 (LAG3), wherein the first antigen binding domain specifically binding to PD 1 comprises a VH domain comprising
(i) HVR-Hl comprising the amino acid sequence of SEQ ID NO: 1,
(ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:2, and
(iii) HVR-H3 comprising an amino acid sequence of SEQ ID NO:3; and
a VL domain comprising
(i) HVR-Ll comprising the amino acid sequence of SEQ ID NO:4;
(ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:5, and
(iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:6.
Codarri Deak teaches methods of treating cancer comprising administering an effective amount of an anti-PD-1/anti-LAG3 bispecific antibody in combination with a T cell activating anti-CD3 bispecific antibody to rescue T cell effector functions from Treg suppression and increase tumor eradication (Abstract; Background; Abstract; Background; page 14, paragraph 4, line 25 and lines 34-35; page 93, lines 20-25). The method includes treating cancers such as leukemia and lymphoma (page 42, lines 21-25). The T cell activating anti-CD3 bispecific antibody has a 2+1 format meaning there are two antigen binding domains comprising the first antigen binding domain and one antigen binding domain for CD3 (page 175, Example 13). The anti-PD-1/anti-LAG3 bispecific antibody comprises a first antigen binding domain that specifically binds PD-1 and a second antigen binding domain that specifically binds to LAG3 (page 4, lines 104). The first antigen binding domain specifically binding to PD-1 comprises a VH domain comprising HVR-H1, HVR-H2, and HVR-H3 comprising amino acid sequence of SEQ ID NOs:1, 2, and 3 respectively (Reference SEQ ID NOS:1-3 match 100% in sequence and length to the instant application’s SEQ ID NOs:1-3) and a VL domain comprising HVR-L1, HVR-L2, and HVR-L3 comprising amino acid sequence of SEQ ID NOs:4, 5, and 6 respectively (Reference SEQ ID NOS:4-6 match 100% in sequence and length to the instant application’s SEQ ID NOs:4-6) (page 4, lines 5-14). Additionally, Codarri Deak teaches the second antigen binding domain that specifically binds to LAG3 comprising a VH domain comprising HVR-H1, HVR-H2, and HVR-H3 comprising amino acid sequence of SEQ ID NOs:14, 15, and 16 respectively (Reference SEQ ID NOS:14-16 match 100% in sequence and length to the instant application’s SEQ ID NOs:11-13) and a VL domain comprising HVR-L1, HVR-L2, and HVR-L3 comprising amino acid sequence of SEQ ID NOs:17, 18, and 19 respectively (Reference SEQ ID NOS:17-19 match 100% in sequence and length to the instant application’s SEQ ID NOs:14-16) (page 4, lines 20-25). Codarri Deak teaches a first Fab fragment specifically binding PD-1 comprising a VH domain comprising SEQ ID NO:9 and a VL domain comprising SEQ ID NO:10 and a second Fab fragment specifically binding LAG3 comprising a VH domain comprising SEQ ID NO:20 and a VL domain comprising SEQ ID NO:21 (SEQ ID NOs:9-10 and 20-21 match 100% in sequence and length to instant application’s SEQ ID NOs:9-10 and 17-18) (page 7, lines 17-24). Codarri Deak teaches the anti-PD-1/anti-LAG3 bispecific antibody and T cell activating CD3 bispecific antibody administered together in a single composition or separately and administered intravenously or subcutaneously (page 85, lines 126-28; page 95, lines 11-15). Finally, Codarri Deak teaches the administration of the anti-PD-1/anti-LAG3 bispecific antibody being administered prior to, simultaneously, and/or following the administration of additional therapeutic agents including the T cell activating CD3 bispecific antibody (page 95, lines 11-15).
However, Codarri Deak does not teach the method of treating CD20 expressing cancer comprising an anti-CD20/anti-CD3 antibody of claims 26-28 and 30-32 .
Varghese does teach a method for treating B-cell cancers which express CD20 comprising administering a PD-1 antibody and a CD20/CD3 bispecific antibody wherein the therapies are delivered subcutaneously or intravenously (Varghese; Abstract; Background, [0004]; [0080]). Varghese teaches that there is an unmet need for therapies in B-cell cancers that are effective, prevent relapse, and have less side effects compared to chemotherapy (Varghese; Background, [0004]). PD-1 antibodies can help overcome these limitations PD-1 plays a key role in allowing tumor cells to escape immune surveillance by the host immune system and PD-1 blockage shows clinical efficacy in patients with aggressive B-cell cancers (Varghese; Background, [0005], [0007]). The PD-1 antibody and CD20/CD3 bispecific antibody combination therapy delayed tumor growth in mice (Varghese; Example 1 and 3; Figures 1 and 3). Varghese additionally teaches a third therapeutic agent, a LAG3 antibody, can be used in combination with the PD-1 antibody and CD20/CD3 bispecific antibody (Varghese; [0046]).
Maruhashi additionally teaches LAG3 contributes to immune escape mechanisms in tumors similar to PD-1 and provides a rationale for combining PD-1 and LAG3 treatment in cancer as LAG-3 and PD-1 act synergistically to suppress antitumor immunity and are promising therapeutic targets for cancer immunotherapy (Maruhashi; page 5, right column, paragraphs 1-2).
It would have been prima facie obvious to one of ordinary skill, in the art as of the effective filing date, to have modified the method of treating cancer comprising administering an anti-PD-1/LAG-3 bispecific antibody in combination with a T cell activating CD3 bispecific antibody of Codarri Deak with the method of treating B-cell cancers which express CD20 comprising administering a PD-1 antibody and a CD20/CD3 bispecific antibody with a LAG-3 inhibitor of Varghese with the rationale to combine PD-1 and LAG3 therapy of Maruhashi with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to make this modification before the effective filing date of the instant invention since Codarri Deak teaches an anti-PD-1/anti-LAG3 bispecific antibody and a T cell activating CD3 bispecific antibody in combination is effective in treating cancers and Varghese teaches the combination of PD-1 antibody and CD20/CD3 bispecific antibody in B-cell malignancies where PD-1 helps overcome tumor cell’s ability to evade the host’s immune system and works synergistically with the CD20/CD3 bispecific antibody to decrease tumor growth and LAG3 antibodies can be used as a third therapeutic option. Additionally, Maruhashi teaches PD-1 and LAG-3 antibodies work synergistically to suppress antitumor immunity.
Therefore, it would have been obvious to combine these elements according to known methods to yield predictable results to suppress antitumor immunity and provide more effective, non-chemotherapy treatments to prevent relapse in CD20 expressing cancer patients.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Claim(s) 26 and 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Codarri Deak and Varghese, further in view of Bacac et al (PTO-892; page 4, Reference V; "Bacac").
Codarri Deak and Varghese teach a method for treating CD20 expressing cancers comprising administering an effective amount of an anti-CD20/anti-CD3 antibody and an effective amount of an anti-PD1/anti-LAG3 bispecific antibody as applied above.
However, Codarri Deak and Varghese do not teach wherein the anti-CD20/anti-CD3 antibody is glofitamab of claims 26 and 29.
Bacac teaches the limitations associated with current anti-CD20 monoclonal antibody therapy where half of NHL patients will not sustain a durable response to standard of care treatment and there is a need for safer and more effective therapies (Bacac; Paragraph 1). Bacac teaches a new class of T-cell bispecific antibodies that promote the activation of a patient’s own T cells to attack and kill cancer cells wherein the antibody is a 2:1 T cell bispecific antibody (CD20-TCB) for treatment of B cell malignancies where the molecule comprises two CD20 binding Fabs and one CD3 epsilon binding Fab (CD20-TCB is the same molecule as the instant application’s glofitamab; see specification page 45, lines 8-9) (Bacac; Paragraph 1). Bacac teaches the CD20-TCB showing promising anti-tumor activity and ability to modify the tumor immune microenvironment and when compared to other CD20 TCBs with a conventional “1:1” IgG format demonstrated superior potency (Bacac; paragraphs 4-5). Bacac additionally teaches the CD20 TCB up-regulating PD-1 and PD-L1 and combination studies of CD20-TCB with a PD-L1 antibody led to more profound and faster tumor growth inhibition (Bacac; paragraphs 4).
It would have been prima facie obvious to one of ordinary skill, in the art as of the effective filing date, to have modified the method of treating CD20 expressing cancer comprising administering an effective amount of an anti-CD20/anti-CD3 antibody and an effective amount of an anti-PD1/anti-LAG3 bispecific antibody of Codarri Deak and Varghese with glofitamab of Bacac with reasonable expectation of success.
One of ordinary skill in the art would have been motivated to make this modification before the effective filing date of the instant invention since Bacac teaches glofitamab to be superior at reducing tumor growth in comparison to other anti-CD20 monoclonal antibodies and anti-CD20/anti-CD-3 bispecific antibodies and can be used in combination with immune checkpoint blockades with clinical efficacy. Therefore, it would have been obvious to combine these elements according to known methods to yield predictable results to more effectively target CD20 and CD3 and improve patient response and outcomes.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence on the contrary.
Conclusion
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/LEAH ELIZABETH STEIN/ Examiner, Art Unit 1641
/NORA M ROONEY/Primary Examiner, Art Unit 1641