Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on 03-26-26 is acknowledged. The traversal is on the ground(s) that (1) Geuijen does not teach or suggest that the multispecific antibody of the claimed method would be effective to treat cancer in a subject in need thereof at the claimed dose and dosing regimen and (2) that M.P.E.P. 803 states that if the search and examination of all the claims in an application can be made without serious burden, the examiner must examine them on the merits, even though they include claims to independent or distinct inventions. Applicant respectfully asserts that it would not be an undue burden for the Office to examine the claims of Groups I and II as set forth in the unity of invention requirement. This is clearly evident as Groups I and II differ only in that Group I includes claims 18 and 20 while Group II does not, and Group II includes claims 16 and 17 while Group I does not.
As to argument (1), this is not found persuasive as applicants did not cite specific arguments addressing the teachings of Geuijen et al. As to argument (2), this is found persuasive and Groups I and II are rejoined as well as Group IV (Claims 61-62- drawn to the kit). Applicants elected the species (without traverse) of SEQ ID: 49 (heavy chain variable domain specific for CD137), SEQ ID NO: 67 (heavy chain variable domain specific for PD-L1 and its corresponding set of 3 CDRs specific to PD-L1:CDR1 (SEQ ID NO: 68); CDR2 (SEQ ID NO: 55); CDR3 (SEQ ID NO: 56).
Claims 2-4, 9-10, 14, 16-23, 30-31, 34-35, 39, 41-42, 47-49, and 59-62 are pending and under consideration.
Claim Objections
Claim 3 is objected to for reciting “MSI” the first time it is used. It is suggested that the claim be amended to: microsatellite instability high (MSI-high) alterations.
Claim 62 is objected to for reciting “in any one the indications” as this is grammatically unclear.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-4, 9-10, 14, 16-23, 30-31, 34-35, 41-42, and 59-62 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 2 and 35 are indefinite for requiring CDR sequences (CDR1, CDR2, CDR3) without specifying the particular sequences associated with each CDR or the method by which they are meant to be determined (e.g. Chothia, Kabat, IGMT, etc.). The recited SEQ ID NOs in the claims correspond to variable heavy regions sequences, and it is unclear which subsequences thereof are intended to correspond to which CDR. Although the disclosure supplies some examples of certain CDRs [0133], it is unclear what is intended to be encompassed by the claimed CDR sequences or how one is to determine the metes and bounds for each of CDR1, CDR2, and CDR3. Claims 3-4, 9-10, 14, 16-23, 30-31, 34, and 59-62 are also rejected as all depend from claim 2 in the absence of defining the CDRs of Claim 2.
Regarding claims 3-4, 41-42, and 62, the phrase "in particular" or “more in particular” renders the claims indefinite because it is unclear whether the limitations following the phrase(s) are part of the claimed invention. See MPEP § 2173.05(d).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 30 and 49 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 30/49 broaden(s) the scope of claim 2 by including SEQ ID NO:49 or variants thereof. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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.
Claim(s) 2-4, 9-10, 14, 16-23, 30-31, 34, 39, 41-42, 47-49, and 59-60 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2018056821 (Geuijen et al., published 03/2018, applicant’s IDS) in view of the teachings of Altintas et al. (WO 2019/025545, February 2019, IDS). For the purposes of comparing the claims to the prior art, the corresponding US national application of Geuijen et al- US 2020/0017595 will be used.
As to claims 2-4, 14, 19, 30, Geuijen et al. teach [0012] a multispecific antibody that comprises an antigen binding site that binds an extracellular part of a member for the TNF receptor superfamily (CD137) and an antigen binding site that can bind an extracellular part of a second membrane protein wherein the second membrane protein is PD-L1. The reference further teaches [0187] treating cancers such as colorectal cancer; pancreatic cancer; lung cancer; breast cancer; liver cancer; prostate cancer; ovarian cancer; cervical cancer; endometrial cancer; head and neck cancer; melanoma; testis cancer; urothelial cancer; renal cancer; stomach cancer; or carcinoid cancer. Further, the multispecific antibody comprises a variable domain that binds to an extracellular part of CD137 wherein the heavy chain variable region comprises SEQ ID NO:49 (elected species).
CC PN WO2018056821-A1.
XX
CC PD 29-MAR-2018.
XX
CC PF 22-SEP-2017; 2017WO-NL050634.
XX
PR 23-SEP-2016; 2016EP-00190499.
XX
CC PA (MERU-) MERUS NV.
XX
CC PI Geuijen CAW, Throsby M, De Kruif CA, Klooster R, Tacken PJ;
CC PI Logtenberg T;
XX
DR WPI; 2018-256494/25.
XX
CC PT Stimulating activity of a TNF receptor unit involves providing a first
CC PT cell and a second cell, where the first cell has unit on the cell
CC PT membrane and the second cell has a second unit protein on the cell
CC PT membrane.
XX
CC PS Example 2; SEQ ID NO 129; 277pp; English.
XX
CC The present invention relates to a method for stimulating the activity of
CC a TNF receptor superfamily (TNFRSF) in a cell. The method involves
CC contacting the cell with a bispecific antibody. The invention further
CC discloses: (1) a bispecific antibody comprising a CD137 extracellular
CC region-binding site, and a second membrane protein-binding site; (2) a
CC composition or kit comprising the bispecific antibody; (3) a method for
CC stimulating the activity of CD137 in a cell by contacting the cell with
CC the bispecific antibody; (4) a bispecific antibody or its functional part
CC capable of binding to CD137 and PD-L1; and (5) a method for treating
CC cancer (preferably colorectal cancer) in a subject. The present sequence
CC is an anti-CD137 Ab heavy chain variable region MF6797, which is useful
CC in preparing a bispecific antibody for stimulating the activity of a TNF
CC receptor superfamily (TNFRSF) in a cell.
XX
SQ Sequence 124 AA;
Query Match 100.0%; Score 670; Length 124;
Best Local Similarity 100.0%;
Matches 124; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QITLKESGPTLVKPTQTLTLTCTFSGFSLSTTGVGVNWIRQPPGEALEWLALIYWNDDTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QITLKESGPTLVKPTQTLTLTCTFSGFSLSTTGVGVNWIRQPPGEALEWLALIYWNDDTY 60
Qy 61 YSPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHEGIIGFLGGNWFDPWGQGTLV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YSPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHEGIIGFLGGNWFDPWGQGTLV 120
Qy 121 TVSS 124
||||
Db 121 TVSS 124
As to claim 16-17, Geuijen et al. teach [0157] that in some embodiments, the domain that comprises an antigen binding site that binds the TNF receptor superfamily member comprises a variable domain that blocks the binding of CD137 to CD137L. Further, regarding claim 17, the reference states that the domain that comprises an antigen binding site that binds the TNF receptor superfamily member comprises a variable domain that blocks the binding of CD137 to CD137L, said variable domain being further characterized by the fact that, “when provided in a monospecific bivalent antibody comprising two of said variable domains, it does not stimulate activity of CD137 on a cell.”
As to claim 18 and 20, Geuijen et al. teach [0153] a method of stimulating activity of a member of the TNF receptor superfamily on a cell comprising providing a first cell and a second cell, wherein said first cell has said member of the TNF receptor superfamily on the cell membrane and said second cell has a second membrane protein on the cell membrane, the method comprising contacting said cells with an antibody or a functional part, derivative and/or analogue thereof that comprises two variable domains, wherein one variable domain comprises a first antigen binding site that can bind an extracellular part of said member of the TNF receptor superfamily (e.g., CD137) and another variable domain comprises a second antigen binding site that can bind an extracellular part of said second membrane protein, thereby stimulating activity of said member on said first cell; wherein said second membrane protein is a member of the B7 family, preferably PD-L1. In some embodiments, said method is an in vitro method.
As to claims 21-23, Geuijen et al. teach [0029] that the binding molecule is preferably a bispecific antibody wherein the method comprises contacting said cells with a bispecific antibody that comprises two variable domains, wherein one variable domain comprises a first antigen binding site that can bind an extracellular part of said first membrane protein and another variable domain comprises a second antigen binding site that can bind an extracellular part of said second membrane protein. Regarding claim 22, These bispecific or multispecific antibodies can be “full length” antibodies- [0102] and [0109] including those that lack Fc effector function but still maintain the “Y” shaped structure- two Fab arms for antigen binding and one Fc region. For example, Geuijen et al. teach [0133] that antibodies with reduced effector functions are preferably IgG antibodies comprising a modified CH2/lower hinge region, for instance to reduce Fc-receptor interaction or to reduce C1q binding. In some embodiments the antibody of the invention is an IgG antibody with a mutant CH2 and/or lower hinge domain such that interaction of the bispecific IgG antibody to an Fc-gamma receptor is reduced.
As to claim 31 and 34, Geuijen et al. teach that the antibody comprises a heavy chain variable region that binds an extracellular part of PD-L1 comprising a CDR3 region of SEQ ID NO:56, a CDR2 region of SEQ ID NO:55 and a CDR region of SEQ ID NO:68 (applicant’s elected species of CDRs); wherein the antibody comprises a heavy chain variable region that binds an extracellular part of PD-L1 comprising/having an amino acid sequence of SEQ ID NO:67 or variants thereof (Applicant’s elected species). Boxed regions below are CDRs.
CC PN WO2018056821-A1.
XX
CC PD 29-MAR-2018.
XX
CC PF 22-SEP-2017; 2017WO-NL050634.
XX
PR 23-SEP-2016; 2016EP-00190499.
XX
CC PA (MERU-) MERUS NV.
XX
CC PI Geuijen CAW, Throsby M, De Kruif CA, Klooster R, Tacken PJ;
CC PI Logtenberg T;
XX
DR WPI; 2018-256494/25.
XX
CC PT Stimulating activity of a TNF receptor unit involves providing a first
CC PT cell and a second cell, where the first cell has unit on the cell
CC PT membrane and the second cell has a second unit protein on the cell
CC PT membrane.
XX
CC PS Example 2; SEQ ID NO 152; 277pp; English.
XX
CC The present invention relates to a method for stimulating the activity of
CC a TNF receptor superfamily (TNFRSF) in a cell. The method involves
CC contacting the cell with a bispecific antibody. The invention further
CC discloses: (1) a bispecific antibody comprising a CD137 extracellular
CC region-binding site, and a second membrane protein-binding site; (2) a
CC composition or kit comprising the bispecific antibody; (3) a method for
CC stimulating the activity of CD137 in a cell by contacting the cell with
CC the bispecific antibody; (4) a bispecific antibody or its functional part
CC capable of binding to CD137 and PD-L1; and (5) a method for treating
CC cancer (preferably colorectal cancer) in a subject. The present sequence
CC is an anti-PDL1 Ab heavy chain variable region MF5553, which is useful in
CC preparing a bispecific antibody for stimulating the activity of a TNF
CC receptor superfamily (TNFRSF) in a cell.
XX
SQ Sequence 125 AA;
Query Match 99.4%; Score 667; Length 125;
Best Local Similarity 99.2%;
Matches 124; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
[AltContent: rect][AltContent: rect]
Qy 1 QVQLVQSGSELKKPGASVKVSCKASGYTFTNYAINWVRQAPGQGLEWMGWINPNTGNPTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGSELKKPGASVKVSCKASGYTFTNYAINWVRQAPGQGLEWMGWINPNTGNPTY 60
[AltContent: rect][AltContent: rect]
Qy 61 AQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARDRKYVTNWVFAEDFQHWGRGTL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||:|||
Db 61 AQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARDRKYVTNWVFAEDFQHWGQGTL 120
Qy 121 VTVSS 125
|||||
Db 121 VTVSS 125
Regarding Claim 39, 41-42, and 49 as set forth above, Geuijen et al. taught methods of treating cancer with the variable domain CDRs (SEQ ID 68, 55, and 56) of the antigen binding site to PD-L1. Geuijen et al. also teaches the variable domain CDRs comprising SEQ IDs: 25, 26, and 27 that bind to an extracellular part of CD137. See below:
WO2018056821-A1.
XX
CC PD 29-MAR-2018.
XX
CC PF 22-SEP-2017; 2017WO-NL050634.
XX
PR 23-SEP-2016; 2016EP-00190499.
XX
CC PA (MERU-) MERUS NV.
XX
CC PI Geuijen CAW, Throsby M, De Kruif CA, Klooster R, Tacken PJ;
CC PI Logtenberg T;
Query Match 87.4%; Score 170.4; Length 122;
Best Local Similarity 43.2%;
Matches 35; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 ELSMH--------------SFYPEDGETIYAQKFQG------------------------ 22
||||| |||||||||||||||||
Db 31 ELSMHWVRQSPGKGLEWMGSFYPEDGETIYAQKFQGRITMTEDTSADTAYMELSSLRSED 90
Qy 23 --------EGVGVIRGNWFDP 35
|||||||||||||
Db 91 TAVYYCATEGVGVIRGNWFDP 111
Claim 49 is identical in scope to claim 30 (taught SEQ ID NO:49) and claim 34 (taught SEQ ID NO:67 or variants thereof) addressed above.
Regarding Claim 59, Geuijen et al. teach [0113 and Figure 1B] that bispecific antibodies as described herein preferably comprise a common light chain variable domain, preferably a common light chain. Figure 1B is 100% identical to the claimed SEQ ID NO:110 and Figure 1A is 100% identical to SEQ ID NO:109.
Regarding Claim 60, Geuijen et al. teach (Figure 2B) a CH1 domain comprising SEQ ID NO:112. Geuijen et al. teach (Figure 2D) a CH2 domain comprising SEQ ID NO:114. Geuijen et al. teach (Figure 2F) a CH3 domain comprising SEQ ID NO:115 and/or a CH3 domain comprising SEQ ID NO:116 (Figure 2G).
Geuijen et al. does not specifically teach “wherein the multispecific antibody is administered in a dose of between 10-50 mg; and wherein the multispecific antibody is administered once every week, once every two weeks, or once every three weeks (Claims 2, 10, and 48). Geuijen et al. also does not teach that the multispecific antibody is administered intravenously (Claims 9, 47).
Altintas et al. also teaches methods of treating cancer with bispecific or multispecific antibodies that bind to the same antigens as currently claimed: bind to human PD-L1 and human CD137 (page 1, 1st paragraph). Altintas et al. teach (page 82) that a physician or veterinarian having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the binding agent (e.g. a bispecific antibody) employed in the pharmaceutical composition at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. The reference further teaches (pages 81-82) that administration can be intravenous and that dosage can range from 0.001-10 mg/kg or 0.1-50 mg/kg. The reference further teaches (page 82) that the binding agent may be administered in a “weekly” dosage such as from 4 to 6 times when given once a week.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to have modified the teachings of Geuijen et al. so as to include the dosing schedules and routes of administration as taught by Altintas et al. One would have been motivated to do so because both teachings are directed to methods of treating cancer using similar bispecific antibodies that bind to human CD137 and PD-L1. Further, MPEP § 2144.05(II)(A) states, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses, and one of ordinary skill in the art would have arrived at intravenous administration at the dosage of 10-50 mg, including once every two weeks, of the bispecific antibody through the process of routine optimization.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 61-62 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2018056821 (Geuijen et al., published 03/2018, applicant’s IDS). For the purposes of comparing the claims to the prior art, the corresponding US national application US 2020/0017595 will be used.
Claims 61 and 62 are drawn to a kit comprising the multispecific antibody of Claim 2 and instructions for use. It is noted that textural instructions are not given patentable weight because textural print matter is not patentable and does not confer patentability on an otherwise anticipated invention. For example, in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals. In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864. See MPEP 2111.05. Thus, the claims encompass the structural components of the antibody which Geuijen et al. taught as set forth above in paragraph/item 14.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643
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