DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed September 3, 2025 is pending.
Claims 35 and 36 are cancelled.
Claims 1-34 and 37-48 are pending.
Election/Restriction
Applicant’s election of Group I (claims 1-41, drawn to a method of suppressing tumor growth in a subject having cancer, comprising: administering a triggering receptor expressed on myeloid cells-2 (TREM2) inhibiting agent and an immunotherapy to a subject in an amount effective to suppress tumor growth); and the species of anti-TREM2 antibody as the TREM2 inhibiting agent and sarcoma as the cancer in the reply filed on September 3, 2025 is acknowledged.
It is noted that because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 42-48 have been withdrawn under 37 CFR 1.142(b) as being drawn to a nonelected group.
Claims 1-34 and 37-41 are currently under consideration.
Priority
Applicant’s claim for domestic benefit to PCT/US2021/019914 filed on February 26, 2021 is acknowledged and provisional applications 63/036,121 filed on June 8, 2020 and 62/981,827 filed on February 26, 2020 is acknowledged. Claims 1-34 and 37-41 are being examined with an effective filing date of February 26, 2020.
Nucleotide and/or Amino Acid Sequence Disclosures
It is noted that the Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. The applicant has not recited the name of the ASCII file (17802631_1_1.txt), its date of creation (August 26, 2022), or its size (55,884 bytes) in the incorporation by reference to the sequence listing paragraph on page 1 of the instant specification. The applicant is required to explicitly reference:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
Applicant is reminded that in order to amend the specification, applicant must provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 20 is objected to because of the following informalities: claim 20 recites “…amount sufficient to make tumor microenvironment...” when it should recite “…amount sufficient to make the tumor microenvironment...” Appropriate correction is required.
Claim Rejections - 35 USC § 112
Improper Dependency
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 3 and 15 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.
Claim 3 recites “wherein the TREM2 inhibiting agent comprises a loss of function mutation in the Fc region or Fc domain to result in a reduction or loss of Fc effector function” in lines 1-3. Claim 3 is dependent on claim 2 which recites “wherein the TREM2 inhibiting agent comprises a mutant or dysfunctional Fc region or Fc domain, resulting in a loss or reduced effector function” in lines 1-3. Thus, the limitations of claims 2 and 3 are substantially the same and therefore, claim 3 does not further limit claim 2. Claims 2 and 3 are both drawn to Fc region mutants that have a reduction or loss of Fc effector function.
Claim 15 recites “wherein the TREM2 inhibiting agent targets, inhibits, prevents, reduces, or blocks TREM2 function” in lines 1 and 2. Claim 15 is dependent on claim 1 which recites “wherein the TREM2 inhibiting agent has TREM2 inhibiting function” in line 6. The functions of targeting, inhibiting, preventing, reducing, or blocking are all TREM2-targeted inhibiting functions. Since claim 1 already recites that the TREM2 inhibitor has TREM2 inhibiting function, the recitation of the TREM2 inhibitor’s ability to target, inhibit, prevent, reduce, or block TREM2 function in claim 15 does not further limit the subject matter of claim 1.
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.
Indefinite Language
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7, 12, and 16 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.
Claim 7 recites the phrase “LALAPG mutations” in line 2. Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The Examiner believes that the phrase “LALAPG mutations” in claim 7 is used by the Applicant to describe mutations that abrogate Fc effector function, namely L234A, L235A, and P329G. However, it is unclear based on the disclosure what exactly “LALAPG mutations” are because the specification fails to clearly redefine the term. Thus, the phrase “LALAPG mutations” is indefinite.
For the purposes of applying prior art, the phrase “LALAPG mutations” is being interpreted as the mutations L234A, L235A, and P329G which are known to abrogate Fc effector function.
Claim 12 recites the limitation “wherein the TREM2 inhibiting agent comprises 21E10 mAb or mAb 178, or a functional fragment or variant thereof” in lines1 and 2.
The claim is indefinite in the recitation of “21E10 mAb” and “mAb 178” because their characteristics are not known. The use of “21E10 mAb” and “mAb 178” as the sole means of identifying the claimed antibody renders the claim indefinite because “21E10 mAb” and “mAb 178” are merely a laboratory designation which does not clearly define the claimed product, since different laboratories may use the same designations to define completely distinct biological materials.
Amending claim 12 to recite the appropriate Deposit Accession Number or SEQ ID NOs would obviate this rejection. See the rejection under the first paragraph of 35 U.S.C. 112 for the deposit of biological materials below.
For the purposes of applying prior art, the terms “21E10 mAb” and “mAb 178” are being used as the names of anti-TREM2 antibodies.
Regarding claim 16, the phrase "optionally" in line 3 renders the claim indefinite because it is unclear whether the limitation(s) following the phrase is part of the claimed invention. See MPEP § 2173.05(d).
Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. In those instances where it is not clear whether the claimed narrower range is a limitation, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph should be made. The examiner should analyze whether the metes and bounds of the claim are clearly set forth. Note that the mere use of the phrase "optionally,” “such as,” or “for example” in a claim does not by itself render the claim indefinite.
Examples of claim language which have been held to be indefinite because the intended scope of the claim was unclear are:
(A) "R is halogen, for example, chlorine";
(B) "material such as rock wool or asbestos" Ex parte Hall, 83 USPQ 38 (Bd. App. 1949);
(C) "lighter hydrocarbons, such, for example, as the vapors or gas produced" Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949);
(D) "normal operating conditions such as while in the container of a proportioner" Ex parte Steigerwald, 131 USPQ 74 (Bd. App. 1961); and
(E) "coke, brick, or like material". Ex parte Caldwell, 1906 C.D. 58 (Comm’r Pat. 1906).
The above examples of claim language which have been held to be indefinite are fact specific and should not be applied as per se rules. See MPEP § 2173.02 for guidance regarding when it is appropriate to make a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
While a single claim that includes the phrase “optionally” may be indefinite, it is not improper under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C.112, second paragraph, to present a dependent claim that sets forth the preferred embodiment in the claim from which it depends. For example, if claim 1 reads "A circuit … wherein the resistance is 70-150 ohms." and claim 2 reads "The circuit of claim 1 wherein the resistance is 70-100 ohms.", then claim 2 should not be rejected as indefinite.
The use of the exemplary language, “optionally,” in claim 16 has rendered the claim indefinite because it is unclear whether the limitation: “T-cells,” following the phrase “optionally” are part of the claimed invention. Therefore, claim 16 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
To obviate this part of the rejection, a limitation that follows the word “optionally” should be claimed in a dependent claim.
For the purposes of applying prior art, the limitations following the word “optionally” are not being considered.
Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 12 is rejected under 35 U.S.C. 112, first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 12 recites the limitation “wherein the TREM2 inhibiting agent comprises 21E10 mAb or mAb 178, or a functional fragment or variant thereof” in lines1 and 2.
It is apparent that the hybridomas that produce the 21E10 mAb and mAb 178 are required to practice the claimed invention. As a required element, the 21E10 mAb and mAb 178 hybridomas must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. If it is not so obtainable or available, the enablement requirements of 35 USC 112, first paragraph, may be satisfied by a deposit of the cell lines/hybridomas which produce the 21E10 mAb and mAb 178. See 37 CFR 1.1801-1.1809.
If the deposit has been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the 21E10 mAb and mAb 178 hybridomas have been deposited under the Budapest Treaty and that the 21E10 mAb and mAb 178 hybridomas will be irrevocably and without restriction or condition released to the public upon the issuance of a patent, would satisfy the deposit requirement made herein. See 37 CFR 1.808.
Further, the record must be clear that the deposit will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent whichever is longer. See 37 CFR 1.806.
If the deposit has not been made under the Budapest treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature must be made, stating that the deposit has been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
If the deposit was made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate the fact, and should state, that the 21E10 mAb and mAb 178 hybridomas, which are deposited, are biological material specifically identified in the application as filed, except if the person is an attorney or agent registered to practice before the Office, in which case the statement need not be verified. See MPEP 1.804(b). Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposit is identical to the biological material described in the specification and in the applicant’s possession at the time the application was filed.
Further, amendment of the specification to disclose the date of deposit and the complete name and address of the depository (ATCC.10801 University Boulevard, Manassas, VA 20110-2209) is required as set forth in 37 C.F.R. 1.809(d). As an additional means for completing the record, applicant may submit a copy of the contract with the depository for deposit and maintenance of each deposit.
It is apparent that the 21E10 mAb and mAb 178 are required to practice the claimed invention. It is noted that the Applicant has provided the nucleic acid sequences encoding the heavy and light chain regions of 21E10 mAb (e.g. SEQ ID NOs: 1 and 2, respectively, see page 21, line 9 – page 22, line 14) and mAb 178 (e.g. SEQ ID NOs: 5 and 6, respectively, see page 23, line 9 – page 24, line 3).
It is noted that the sequence of an entire immunoglobulin satisfies the enablement requirements under 35 USC 112, first paragraph as well. Note that satisfaction for the enablement of biological deposit of the specific 21E10 mAb and mAb 178 requires the disclosure and recitation of their entire amino acid sequence and not based upon partial sequences.
Applicant is invited to make the record clear whether satisfaction of the requirements under 35 USC 112, first paragraph, enablement for biological materials has been satisfied in a current U.S. Patent for “21E10 mAb” and “mAb 178” in order to make the record of the instant application complete.
Written Description
Claims 1-34 and 37-41 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 contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a method of suppressing tumor growth in a subject having cancer, comprising: administering a TREM2 inhibiting agent and an immunotherapy to a subject in an amount effective to suppress tumor growth, wherein the TREM2 inhibiting agent comprises an antibody or a functional fragment or variant thereof.
To support such TREM2 inhibiting agents, the instant specification discloses several examples of the claimed method which incorporates only three species of anti-TREM2 antibodies: 21E10 mAb, mAb 178, and mAb 29E3. Examples 1-3 are working examples and Example 4 is a prophetic example.
The Applicant has provided the nucleic acid sequences encoding the heavy and light chain regions of the 21E10 mAb (e.g. SEQ ID NOs: 1 and 2, respectively, see page 21, line 9 – page 22, line 14), the 29E3 mAb (e.g. SEQ ID NOs: 3 and 4, respectively, see page 22, line 15 – page 22, line 8), and mAb 178 (e.g. SEQ ID NOs: 5 and 6, respectively, see page 23, line 9 – page 24, line 3).
There is insufficient written description encompassing any TREM2 inhibiting agent comprising an antibody or a functional fragment or variant thereof which specifically binds to and inhibits TREM2; or those wherein the antibody or a functional fragment or variant thereof is a monoclonal antibody (mAb) (claims 9-11) or 21E10 mAb or mAb 178 (claim 12); or wherein the in the TREM2 inhibiting agent is a TREM2 neutralizing antibody or functional fragment or variant thereof expressed on a CAR T-cell (claim 41). The genus and subgenera of TREM2 inhibiting agents, as currently recited in the instant claims, do not have sufficient written description because they do not have relevant identifying characteristics, such as structure or other physical and/or chemical characteristics, as currently disclosed. The “TREM2 inhibiting agents” encompass distinct and diverse structures and do not encompass common structural elements essential to the common utility of binding to and inhibiting TREM2.
Triggering receptor expressed on myeloid cells 2 (TREM2) is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer’s disease (e.g. see Molgora et al. 2020 Cell; 182(4), 886-900.e17, an IDS reference filed 06/20/2025, Summary and graphical abstract copied below). TREM2 is also expressed by tumor-infiltrating macrophages. Trem2–/– mice are more resistant to growth of various cancers than wild-type mice and are more responsive to anti-PD-1 immunotherapy. Furthermore, treatment with anti-TREM2 mAb curbs tumor growth and fosters regression when combined with anti-PD-1. scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1+ and CX3CR1+ macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses. TREM2 is expressed in tumor macrophages in over 200 human cancer cases and is inversely correlated with prolonged survival for two types of cancer. Thus, given that checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells, TREM2 is an attractive target for modifying tumor myeloid infiltrates and augmenting checkpoint immunotherapy (e.g. see Molgora et al. 2020, Summary).
It is noted that the applicant has broadly claimed a genus of TREM2 inhibiting agents comprising an antibody or a functional fragment or variant thereof which specifically bind to and inhibit TREM2 to be used in a method of suppressing tumor growth in a subject having cancer. However, the broadest claim (claim 1) does not indicate any specific structure for the genus of TREM2 inhibiting agents. Indeed, dependent claims, such as claims 9-11, 12, and 41, indicate specific subgenera wherein the antibody or a functional fragment or variant thereof is a monoclonal antibody (mAb) (claims 9-11) or 21E10 mAb or mAb 178 (claim 12); or wherein the in the TREM2 inhibiting agent is a TREM2 neutralizing antibody or functional fragment or variant thereof expressed on a CAR T-cell (claim 41), but still fail to recite specific structure.
Despite the Applicant’s disclosure, none of the claims at issue in the instant rejection recite any structural limitations specific to the administered TREM2 inhibiting agents, such as requiring particular CDR or VH and VL sequences. See the rejections of claim 12 under U.S.C. 112(b) and 112(a), enablement, regarding the 21E10 mAb and 178 mAb clones above for an explanation of why claim 12 is drawn to indefinite products which are not enabled. Therefore, 21E10 mAb and 178 mAb would not remedy the lack of written description for the TREM2 inhibiting agents as they are currently claimed.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by 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 (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
Artisans are well aware that knowledge of a given antigen (for instance a TREM2) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document). Similarly, Lloyd et al. (Protein Engineering Design & Selection 2009, 22;3:159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, as their sequencing studies revealed that out of 841 unselected and 5,044 selected antibodies, all but one of the 49 functional VH gene segments was observed (see entire document). Goel et al. (The Journal of Immunology, 2004, 173:7358-7367) disclose the synthesis of three mAbs that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (see entire document).
As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen. Indeed, Kanyavuz et al. (Nature Review Immunology, 2019, 19: 355-368) teach that “Theoretically, under physiological conditions, the human immune system can generate BCRs with 1026 distinct sequences, an astronomical number that is far greater than the calculated number of all B cell clones that can be generated during the lifespan of a healthy human (estimated to be 4 × 1014).
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
The art recognizes that a complete set of six CDRs comprise the binding region of an antibody (see Sela-Culang et al. 2013, Frontiers in Immunology, Volume 4, Article 302, Pages 1-13), and that even a single amino acid change to these regions can completely abrogate the binding specificity of an antibody (see Kussie et al. 1994, Journal of Immunology, Pages 146-152 and Chen et al. 1995, The EMBO Journal, Volume 14, Number 12, Pages 2784-2794). Thus, making changes to the CDR sequence of an antibody is a highly unpredictable process and the skilled artisan could not a priori make any predictions regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions.
As noted above, while the specification does discuss three specific TREM2 inhibiting agents, such a disclosure still does not serve to provide sufficient written description of the claimed genus of TREM2 inhibiting agents comprising an antibody or a functional fragment or variant thereof which specifically binds to and inhibits TREM2. The disclosure does not identify any specific structural features or combination of features which give rise to the function of binding and inhibiting TREM2. Further, there does not appear to be any reasonable shared structure present in the genus of recited “TREM2 inhibiting agents” which gives rise to their functional activity. As such, the instant specification appears to disclose applicant’s wish for TREM2 inhibiting agents that bind and inhibit TREM2 without informing artisans what such TREM2 inhibiting agents actually are.
Ultimately, identifying an antibody simply on the basis of what it binds rather than by identifying the sequence/structure of the antibody in question is generally insufficient to provide written description of the antibody in question.
Therefore, in view of the breadth of the claims and the limited disclosure of species in the instant specification, artisans would reasonably conclude that applicant was not in possession of the full breadth of TREM2 inhibiting agents at the time the instant application was filed.
Amending the claims to recite sufficient structure, namely a complete set of six CDRs, would obviate this part of the rejection.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-6, 8-11, 13-34 and 37-40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Monroe et al. 2017 (US20170240631A1, an IDS reference filed 06/20/2023).
Monroe et al. demonstrate the anti-cancer/anti-tumor effect of anti-TREM2 antibodies and their additive effect when used in combination with Inhibitory Checkpoint Proteins (e.g. see Examples 48 and 49 on [0809]-[0810]). Monroe et al.’s anti-TREM2 antibodies may be composed of antibody variable domains with the desired binding specificities (antibody-antigen combining sites) fused to immunoglobulin constant domain sequences (e.g. see [0358]) and may be monoclonal antibodies (e.g. see claim 31).
Monroe et al. teach that their anti-TREM2 antibodies may be used for preventing, reducing risk, or treating cancer, including, fibrosarcoma (e.g. see [0478]).
Monroe et al. also teach modifying an anti-TREM2 antibody to impair effector function by removing N-glycosylation of the Fc region (e.g., in the CH 2 domain of IgG) or by modifying regions such as 233-236, 297, and/or 327-331 of human IgG (e.g. see [0370]). Such Fc region modifications may include one or more amino acid substitutions, such as L234A, L235A (the LALA mutations), and P329A (e.g. see claim 140).
Regarding the addition of one or more glycosylation sites, Monroe et al. also teach that amino acids can be introduced to the Fc region to alter the original glycosylation pattern of the antibody (e.g. see [0387]). Altering means deleting one or more carbohydrate moieties found in the antibody, and/or adding one or more glycosylation sites that are not present in the antibody (e.g. see [0387]).
Regarding claims 16-29, given that the prior art administered a same anti-TREM2 antibody to the same patients with tumor growth, the prior art anti-TREM2 antibody would inherently have the same functions, e.g. those recited in claims 16-29. These claims recite limitations that are attributable to properties that are inherent to the claimed TREM2 inhibiting agent comprising an antibody or a functional fragment or variant thereof without evidence to the contrary. For example, for the limitation “wherein the TREM2 inhibiting agent modifies tumor-infiltrating myeloid cells to maintain an environment hospitable to immune cells” as recited in lines 1-3 of claim 16, Monroe et al. is silent on these properties. However, silence about a particular property does not necessarily constitute its absence. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the materials, i.e., that the claims are directed to new materials and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter, if new, is unobvious. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Thus, claims 1-6, 8-11, 13-34 and 37-41 are anticipated by Monroe et al.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Monroe et al. 2017 (US20170240631A1, an IDS reference filed 06/20/2023) in view of Schlothauer et al. 2016 (Protein Eng. Des. Sel., 29, 10: 457-466).
The teachings of Monroe et al. are discussed in the 102 rejection above.
The reference teachings differ from the instant invention by not teaching the “PG” part of the LALAPG mutation recited in line 2 of claim 7, namely, a P329G instead of the P329A point mutation.
Schlothauer et al. teach that the Fc region of human IgG antibodies (hIgGs) provides useful attributes for their use as therapeutics, such as a long circulatory half-life and good biochemical and biophysical stability (e.g. paragraph spanning pages 457 and 458). In addition, robust and efficient manufacturing processes adapted for Fc-bearing hIgGs are now commonly used in industry. The Fc region interacts with multiple Fcγ receptor (FcγR) and complement proteins and mediates immune effector functions, which are important for many therapeutic applications, e.g. elimination of targeted cells via antibody-dependent cellular-cytotoxicity (ADCC), -phagocytosis (ADCP) or complement-dependent cytotoxicity (CDC). However, for therapeutic approaches where the mechanism of action is exclusively mediated by the Fab arms or other protein domains fused to the Fc, it may be beneficial to have a silent Fc. Abrogation of Fc/FcγR and complement protein C1q interactions can be desired to prevent unwanted side effects such as infusion reactions and cell as well as tissue damage introduced by FcγR-mediated immune effector functions. Therefore, development of a completely silent Fc portion is of great value for development of therapeutic molecules that do not require FcγR- or C1q-mediated effector function (e.g. paragraph spanning pages 457 and 458).
One approach for the development of therapeutic IgGs with reduced immune effector functions has been to employ various Fc mutations (e.g. see page 458, left column, second paragraph). These include removal of the native Fc N-linked glycosylation site in hIgG1, leucine to glutamic acid substitution at position 235 of the IgG1 Fc, which is within the lower hinge region, and other modifications of the lower hinge within amino acids 234–237. The so-called ‘LALA’ double mutation (Leu234Ala together with Leu235Ala) was first described by the Winter group as a valuable molecule with diminished effector functions. More recently, a variant of the human IgG2 type was described as devoid of detectable FcγR-mediated effector function. However, it involves seven mutations in the constant Fc region, and thus may not be an ideal solution regarding potential immunogenicity (e.g. see page 458, left column, second paragraph).
To provide an ‘effector-silent’ Fc that has a minimum number of mutations in the framework, but is as devoid of effector function as possible, Schlothauer et al., identified a conserved proline sandwich motif at the interface of IgGs and FcγRs (e.g. see page 458, left column, third paragraph). The proline residue at position 329 of the human IgG1 Fc forms van der Waals contacts with the two tryptophans (W108 and W131) of the FcγRIII. This interaction motif is conserved between most Fcγ and Fcε receptors and the four human IgG isotypes as well as the three mouse IgG isotypes and the human IgE sequences (e.g. see page 458, left column, third paragraph). Consequently, the human IgG1-P329G LALA variant is used as an effector silent Fc domain for several therapeutic fusion proteins in several clinical trials (e.g. see page 458, left column, fifth paragraph).
Schlothauer et al. specifically disclose a differentiation between the previously described P329A variant and the novel P329G variant (e.g. see page 464, right column, first paragraph). While the P329A variant has reduced affinity to the receptor, introducing a P329G instead further increases the inertness of the Fc portion, and the combination of this P329G with LALA results in a complete silencing of the FcγR binding. This held true for functional assays like ADCC also (e.g. see page 464, right column, first paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Monroe et al. to incorporate the teachings of Schlothauer et al. to include a P329G point mutation in the Fc instead of the P329A mutation, in combination with the LALA mutations. The value of abrogating Fc/FcγR and complement protein C1q interactions for therapeutic antibodies is well known and desirable for preventing unwanted side effects (Schlothauer et al.). This is accomplished by designing a completely silent Fc portion of therapeutic molecules that do not require FcγR- or C1q-mediated effector function (Schlothauer et al.). It is desirable to design ‘effector-silent’ Fc regions with a minimum number of mutations in the framework that are as devoid of effector function as possible (Schlothauer et al.). As a result the so-called ‘LALA’ double mutation (Leu234Ala together with Leu235Ala) can be combined with a proline to alanine or glycine point mutation at residue 329. It is noted that Monroe et al. already teach the Fc region modifications: L234A, L235A (the LALA mutations) and P329A (e.g. see claim 140). However, Schlothauer et al. explicitly teach that the P329G mutation further increases the inertness of the Fc portion relative to the P329A mutation, and the combination of this P329G with LALA results in a complete silencing of the FcγR binding.
Thus, given the value of ‘effector-silent’ Fc regions in therapeutic antibodies, their design using the “LALA” double mutation in combination with a proline to alanine or glycine point mutation at residue 329, and the preference for the P329G mutation given its enhanced silencing function relative to the P329A; it would have been obvious to a skilled artisan with the goal of designing an ‘effector-silent’ Fc variant of Monroe et al.’s anti-TREM2 antibodies, to combine the “LALA” mutation with the Schlothauer et al.’s P329G mutation with a reasonable expectation of success. Based on Schlothauer et al.’s study, the combination of the P329G mutation with LALA mutations results in a complete silencing of the FcγR binding.
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 to the contrary.
Claims 1, 8, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Monroe et al. 2017 (US20170240631A1, an IDS reference filed 06/20/2023) in view of Turnbull et al. 2006 (J. Immunol., 177, 6: 3520-3524, an IDS reference filed 06/20/2025).
The teachings of Monroe et al. are discussed in the 102 rejection above.
The reference teachings differ from the instant invention by not teaching that the specific TREM2 inhibiting agent is mAb 178 or 21E10 mAb.
Turnbull et al. teach the anti-TREM2 antibody mAb 178 (e.g. see page 3521, left column, first paragraph under “results and discussion”). mAb 178 is specific for murine TREM 2 and was generated in order to study the distribution of TREM2. mAb 178 is specific for TREM-2, because it binds to cells co-transfected with TREM-2 but not to control cells transfected with the related receptor TREM-1 (e.g. see page 3521, left column, first paragraph under “results and discussion”).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Monroe et al. to incorporate the teachings of Turnbull et al. to include that the specific TREM2 inhibiting agent is mAb 178. Given that mAb 178 is specific for TREM2, it would have been obvious to a skilled artisan with the goal of applying an anti-TEM2 monoclonal antibody in Monroe et al.’s method of suppressing tumor growth with a combination of an anti-TREM2 antibody and an immunotherapy, to have selected Turnbull et al.’s anti-TREM2 antibody, mAb 178, with a reasonable expectation of success.
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 to the contrary.
Claims 1 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Monroe et al. 2017 (US20170240631A1, an IDS reference filed 06/20/2023) in view of Srivastava and Riddell 2015 (Trends Immunol. 36, 8; 494-502).
The teachings of Monroe et al. are discussed in the 102 rejection above.
The reference teachings differ from the instant invention by not teaching that the TREM2 inhibiting agent is a TREM2 neutralizing antibody or functional fragment or variant thereof expressed on a CAR-T cell.
Srivastava and Riddell teach that advances in genetic engineering combined with an improved understanding of T cell recognition have led to the design of synthetic tumor targeting receptors, termed chimeric antigen receptors (CARs), that can be introduced into human T cells to redirect antigen specificity and enhance function in adoptive immunotherapy (e.g. see page 494, left column, first paragraph under “introduction”). The basic concept underlying the design of CARs is to link an extracellular ligand recognition domain, typically a single-chain variable fragment (scFv), to an intracellular signaling module that includes CD3ζ to induce T cell activation upon antigen binding. The modular structure has been extended from first-generation CARs with only a CD3ζ signaling domain to second- and third-generation CARs that link the signaling endodomains of CD28, 4-1BB, or OX40 to CD3ζ in an attempt to mimic costimulation (signal 2) that is provided during T cell receptor (TCR) recognition by antigen-presenting cells (APCs) and required for full physiological T cell activation. The approach of providing one or more costimulatory signals in cis in second- and third-generation CARs augments cytokine production and proliferation of CAR-T cells in vitro and second-generation CD19-specific CARs carrying CD28 or 4-1BB signaling moieties have demonstrated potent in vivo antitumor activity in preclinical models and clinical trials for B cell malignancies (e.g. see page 494, left column, first paragraph under “introduction”).
ScFv-based extracellular recognition domains have dominated the synthetic antigen receptor field (e.g. see paragraph spanning pages 499 and 500). Thus, development of new CARs relies heavily on constructing scFvs from murine monoclonal antibody VH and VL sequences specific for tumor-associated molecules from already available hybridomas (e.g. see paragraph spanning pages 499 and 500).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Monroe et al. to incorporate the teachings of Srivastava and Riddell to include that the TREM2 inhibiting agent is a TREM2 neutralizing antibody or functional fragment or variant thereof expressed on a CAR-T cell. Given that CARs are designed by linking an extracellular ligand recognition domain, typically a single-chain variable fragment (scFv), to an intracellular signaling module that includes CD3ζ to induce T cell activation upon antigen binding; it would have been obvious to a skilled artisan to construct an scFv-based extracellular recognition domain of a CAR T-cell from the VH and VL domains of Monroe et al.’s anti-TREM2 antibodies and apply them in the method of suppressing tumor growth with a reasonable expectation of success.
Furthermore, CAR T-cells have the same degree of selective interaction with a target as antibodies do, and thus are able to specifically direct immune responses to a target of interest. Thus, a skilled artisan would reasonably use a CAR T-cell in place of an antibody in Monroe et al.’s method of suppressing tumor growth given the well-established anti-tumor activity of CAR T-cell-based immunotherapies.
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 to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting