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 .
Status of Claims
Please Note: This is a second non-final action issued in response to the November 11, 2025.
Claims 1 - 20 are currently pending. No claims have been amended, added, or canceled by the Applicant’s amendment filed November 11, 2025.
Applicant's election without traverse of Group I, claims 1 - 10, drawn to an engineered immune cell; and the election of Species as follows:
Species (A): wherein binding of the blocking receptors in the first micro-cluster to the cognate blocking ligands on the healthy cell prevents breakup of the first micro-cluster (Claim 5);
Species (B): wherein the activating and blocking receptors form a first micro-cluster in the first region, and the activating and blocking receptors form a second micro-cluster in the second region (Claim 3), in the reply filed 13 September, 2023 were previously acknowledged.
Claims 11 - 20 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 4 and 8 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
The restriction requirement was previously made FINAL.
Response to Arguments
At page 6 of the remarks filed on November 11, 2025 in relation to the species election between of withdrawn claims 4 and 8 , Applicants essentially argue that “Applicant submits that the purported "species" of claim 5, which recites the feature that binding of the blocking receptors in the first micro-cluster to the cognate blocking ligands on the healthy cell prevents breakup of the first micro-cluster is not mutually exclusive of the subject matter of claim 4.”. Applicants’ arguments have been respectfully considered but have not been found persuasive. (Please note: the Examiner has already addressed this argument previously in the office action mailed August 11, 2025.).
The initial restriction requirement filed on 7/13/2023 required selection of species in relation to the effects of binding of the blocking receptors as recited in claims 4 and 5, both claims dependent from claim 3. Applicants elected the species of claim 5, in Applicants’ response filed on 9/13/2023 (see page 5). Therefore, the examiner withdraw claim 4 from consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
Applicant is reminded of the right to petition under 37 CFR 1.144, if applicant disagrees with the species requirements for restriction filed on 07/13/2023.
The claims will be examined insofar as they read on the elected species.
Therefore, claims 1 – 3, 5 – 7, and 9 – 10 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application, filed September 21, 2021, claims benefit of the Provisional Application, 63/081,256, 63/081,229, 63/081,250, 63/081,231, 63/081,242, 63/081,248, 63/081,237, and 63/081,258, all filed on September 21, 2020.
Withdrawn Objections/Rejections
Claim Rejections - 35 USC § 103
The rejection of claims 1– 3, and 9 – 10 under 35 U.S.C. 103 as being unpatentable over
Fedorov et al. (hereinafter referred to as “Fedorov”) (WO 2015/142314 A1, Published on 24 September 2015), and further in view of Maute et al. (hereinafter referred to as “Maute”) (US2019/0241664 A1, published August 8, 2019), as evidenced by Dong et al. (Dong R. et al. Rewired signaling network in T cells expressing the chimeric antigen receptor (CAR). EMBO J. 2020 Aug 17;39(16):e104730. doi: 10.15252/embj.2020104730. Epub 2020 Jul 9. PMID: 32643825; PMCID: PMC7429742.) is withdrawn.
Maute does not specifically teach that that the antibodies include the LILRB1 hinge, and, rather, Maute teaches specific hinge embodiments.
In view of the withdrawn rejection, Applicant’s arguments are moot.
The rejection of claims 6-7 remain under 35 U.S.C. 103 as being unpatentable over Fedorov
and Maute as applied to claims 1 and 2 above, and further in view of Nimmerjahn et al. (hereinafter referred to as “Nimmerjahn”) (Nimmerjahn F. et al. Fcgamma receptors: old friends and new family members. Immunity. 2006 Jan;24(1):19-28. doi: 10.1016/j.immuni.2005.11.010. PMID: 16413920.) as evidenced by Dong (Dong R. et al. Rewired signaling network in T cells expressing the chimeric antigen receptor (CAR). EMBO J. 2020 Aug 17;39(16):e104730. doi: 10.15252/embj.2020104730. Epub 2020 Jul 9. PMID: 32643825; PMCID: PMC7429742) is withdrawn.
Maute does not specifically teach that that the antibodies include the LILRB1 hinge, and, rather, Maute teaches specific hinge embodiments.
In view of the withdrawn rejection, Applicant’s arguments are moot.
Maintained Objections/Rejections
Claim Rejection - 35 USC § 112(b)
The rejection of claims 1 – 3, 5 – 7, and 9 – 10 is maintained 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 1 remains rejected because of the recitation of “a hinge comprising a peptide having a length of between 10 and 64 amino acids and having at least 90% similarity to a continuous amino acid sequence having said length of a hinge of a leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB 1) protein” because there is not sequence provided for the LILRB 1 protein. Therefore, it is unclear in reference to what sequence the peptide having a length of between 10 and 64 amino acids has 90% sequence identity. As such the metes and bounds of the claim are indefinite.
Claim 2 – 3, 5, and 9 – 10 are indefinite insofar as they ultimately depend from claim 1.
Response to Arguments as they apply to rejection of claims 1 under 35 USC § 112(b)
Applicant’s arguments filed November 11, 2025 have been fully considered but they are not persuasive. Applicant essentially asserts (a) one of ordinary skill in the art would be able to determine the hinge domain sequence of LILRB1 as set forth in claim 1 (Remarks, pg. 7, fifth paragraph).
Regarding (a), Applicant’s arguments are not persuasive.
Applicant points out that the Examiner has written that “Maute teaches the LILRB1 sequence (Seq ID No:1). (Please Note: Seq ID No. 1 (the LILRB1 isoform sequence) has an 100% alignment match with instant Seq ID No. 84 (LILRB1 hinge domain).” (Office Action mailed on August 11, 2025, pg. 6). The Applicant concludes that a person of ordinary skill in the art would be able to determine sequence of LILRB1.
However, in response to the office action, the applicant has written that Maute does not suggest that these compounds include the LILRB1 hinge. (Applicant Remarks, pg. 11, last paragraph). Thus, it is still unclear what is the sequence of the LILRB1 hinge, and the rejection is maintained.
New Objections/Rejections
Claim Rejections - 35 USC § 112(a) - Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112, first paragraph:
(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.
Claims 1 – 3, 5 – 7, and 9 - 10 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 1 – 3, 5 – 7, and 9 - 10 encompass an engineered immune cell, comprising activating receptors and blocking receptors on a surface of the blocking receptors comprise a hinge comprising a peptide having a length of between 10 and 64 amino acids and having at least 90% similarity to a continuous amino acid sequence having said length of a hinge of LILRB1 protein, and wherein the engineered immune cell contacts a tumor cell and a healthy cell;
a first region of the activating and blocking receptors forms on the surface of the engineered immune cell proximal to the healthy cell contacting the engineered immune cell, and the blocking receptors in the first region inhibit cytotoxic effects on the healthy cell,
while, simultaneously, a second region of the activating and blocking receptors forms on the surface of the engineered immune cell proximal to the tumor cell contacting the engineered immune cell and promotes a cytotoxic response by the engineered immune cell that exhibits cytotoxic effects on the tumor cell. Overall, what these statements indicate is that the Applicant must provide adequate description of such core structure and function related to that method such that the Artisan could determine the desired effect. Hence, the analysis below demonstrates that Applicant has not determined the core structure and function for full scope of the claimed method.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail such that the Artisan can reasonably conclude that the inventors had possession of the claimed invention. Such possession may be demonstrated by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and/or formulae that fully set forth the claimed invention. Possession may be shown by an actual reduction to practice, showing that the invention was "ready for patenting", or by describing distinguishing identifying characteristics sufficient to show that Applicant was in possession of the claimed invention (January 5, 2001 Fed. Reg., Vol. 66, No. 4, pp. 1099-11). MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description”. Moreover, MPEP 2163 states: [A] biomolecule sequence described only by a functional characteristic, without any known or disclosed characteristic, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function.
In analyzing whether the written description requirement is met for the claimed method, it is first determined whether the examples describe an engineered immune cell comprising activating receptors and blocking receptors on a surface of the cell, wherein the blocking receptors comprise a hinge having a length of between 10 and 64 amino acids, and having at least 90% similarity to a hinge of LILRB1 protein.
The instant claims encompass a genus of engineered cells with the contemplated use of treating cancer. There is not structure/function correlation for the claimed genus of cells. In the instant case, Applicant does not disclose any relevant examples that teach the genus of engineered immune cells that comprise activating receptors and blocking receptors on a surface of the cell, wherein the blocking receptors comprise a hinge having a length of between 10 and 64 amino acids, and having at least 90% similarity to a hinge of LILRB1 protein.
However, Applicant discloses relevant Figures, particularly Figures 25 and 26. Figure 25 provides experimental results showing the relative impact hinge length and flexibility has on the strength of a blocking receptor (Paragraph [0470]). The examiner acknowledges that the figure teaches “2B1,” which refers to the LILRB1 hinge, which is of 64 amino acids. However, it is not clear which Seq ID refers to this 64 amino acid hinge. Additionally, this figure does not show any a LILRB1 of any other length, namely between 10 to 64 amino acid, as required by claim 1. (Further, this figure teaches Seq ID Nos. 392 – 397, which are not included in the Seq Listing of the as-Filed Specification). The as-Filed Specification also teaches Figure 26, wherein 45 separate activating receptors were created by testing 3 different hinges (Paragraph [0471]). However, it is not clear whether the hinge of LILRB1 was used in these receptors.
Further, the as-Filed Specification teaches that
“the receptors having one or more domains isolated or derived from LILRB1, the one or more domains of LILRB1 comprise an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or is identical to a sequence or subsequence of SEQ ID NO: 65, 77, 78, 79, 80, 81, 82, 83, 84, or 85 and/or is encoded by a polynucleotide sequence that is at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or is identical to a sequence or subsequence of SEQ ID NO: 66.” (Paragraph [0343]).
Therefore, it is unclear what exactly the sequence of the hinge of LILRB1 is, and which amino acids are actually used in the hinge domain on the blocking receptors of the instantly filed claims.
These figures do teach engineered immune cells comprising activating and blocking receptors, but it doesn’t teach the genus of engineered immune cells comprising activating receptors and blocking receptors that comprise the hinge of LILRB1.
Before the effective filing date of the claimed invention, it was known in the art that that there was increased phagocytic activity with increased hinge length, as evidenced by Chu et al. (Chu TH et al. PLoS Pathog. 2020 Feb 24;16(2):e1008083. doi: 10.1371/journal.ppat.1008083. PMID: 32092122; PMCID: PMC7058349.) (pg. 7, first paragraph).
It was also known in the art that CARs with a CD8α- or CD28-derived hinge domain showed significant differences in CAR-T cell function, despite their equal expression levels, suggesting that CAR signaling intensity into T cells was affected by the hinge domain, as evidenced by Fujiwara et al. (Fujiwara K. et al. Cells. 2020 May 9;9(5):1182. doi: 10.3390/cells9051182. PMID: 32397414; PMCID: PMC7291079.) (Abstract).
Further, Maute et al. teaches that an anti-LILRB1 antibody (Paragraph [0072]), wherein the antibodies comprise heavy chains that can contain any hinge region sequence found in an intact antibody (Paragraph [0059]). Maute teaches the LILRB1 sequence (Seq ID No:1). (Please Note: Seq ID No. 1 (the LILRB1 isoform sequence) has an 100% alignment match with instant Seq ID No. 84 (LILRB1 hinge domain).
The applicant is on record for saying that Maute does not suggest that these compounds include the LILRB1 hinge, and that Maute discusses specific hinge embodiments (Applicant Remarks, pg. 11, last paragraph). Further, the applicant is on record for saying that the hinges made using LILRB1 derived peptides provide a pronounced and controllable effect on the strength of the receptor’s blocking signal (Applicant Remarks, pg. 10, first paragraph). However, it is still unclear what the exact sequence of the LILRB1 hinge sequence is, and its use in blocking receptors.
Thus, these references indicate that there is a lot of unpredictability in the art pertaining to the sequence of the LILRB1 hinge, the relevance of hinge length, and the hinge itself in the functions and effectiveness of the receptor.
There is no structure/function correlation for all the claimed composition. In the instant case, Applicant does not disclose any relevant examples that teach the composition comprising all the components (the activating receptors, and the blocking receptors that comprise a hinge derived from LILRB1).
Therefore, the specification does not contain a written description of the invention, and a 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 can make and use the same, nor does it set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. This limited information is not deemed sufficient to reasonably convey to one skilled in the art that Applicant is in possession of the composition as recited in the instant claims.
Claim Rejection - 35 USC § 112(a) Scope of Enablement
Claims 1 – 3, 5 – 7, and 9 - 10 are newly 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 engineered immune cells comprising a pair of activating and blocking receptors each comprising a ligand binding domain (LBD), a hinge, a transmembrane domain, and an intracellular domain (ICD), wherein the LBD is a scFV activating receptor for a MAGE-A3 target activating ligand, and the scFV blocking receptor (ESO-Tmod) is a NY-ESO-1 blocking ligand, wherein the hinge of the blocking receptor comprises a peptide having 100% identity to the sequence of a leukocyte immunoglobulin-like receptor subfamily B member I (LILRB I) hinge domain,
does not reasonably provide enablement for using any pair of activating and blocking receptor or target ligand, or using a hinge that comprises a peptide having a length of between 10 and 64 amino acids and having at least 90% similarity to a hinge of LILRB1.
The Specification does not enable any person skill in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The claims, when given the broadest possible interpretation, encompass a method of producing an engineered immune cell, comprising activating receptors and blocking receptors on a surface of the blocking receptors comprise a hinge comprising a peptide having a length of between 10 and 64 amino acids and having at least 90% similarity to a continuous amino acid sequence having said length of a hinge of LILRB1 protein, and wherein the engineered immune cell contacts a tumor cell and a healthy cell;
a first region of the activating and blocking receptors forms on the surface of the engineered immune cell proximal to the healthy cell contacting the engineered immune cell, and the blocking receptors in the first region inhibit cytotoxic effects on the healthy cell,
while, simultaneously, a second region of the activating and blocking receptors forms on the surface of the engineered immune cell proximal to the tumor cell contacting the engineered immune cell and promotes a cytotoxic response by the engineered immune cell that exhibits cytotoxic effects on the tumor cell.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
Nature of invention. The invention encompasses a method of producing an
engineered immune cell, comprising activating receptors and blocking receptors on a surface of the blocking receptors comprise a hinge comprising a peptide having a length of between 10 and 64 amino acids and having at least 90% similarity to a continuous amino acid sequence having said length of a hinge of LILRB1 protein, and wherein the engineered immune cell contacts a tumor cell and a healthy cell;
a first region of the activating and blocking receptors forms on the surface of the engineered immune cell proximal to the healthy cell contacting the engineered immune cell, and the blocking receptors in the first region inhibit cytotoxic effects on the healthy cell,
while, simultaneously, a second region of the activating and blocking receptors forms on the surface of the engineered immune cell proximal to the tumor cell contacting the engineered immune cell and promotes a cytotoxic response by the engineered immune cell that exhibits cytotoxic effects on the tumor cell.
Scope of the invention. The invention encompasses a method of producing an
engineered immune cell that comprises two types of ligand binding receptors to be expressed on the surface of cells.
Number of working examples and guidance. In the instant case, Applicant does not disclose any relevant examples that teach the genus of engineered immune cells comprising any combination of an activating receptor, a blocking receptor and their binding to the activating/blocking ligand (respectively) on a tumor and non-tumor cell, and wherein the hinge of the blocking receptor comprises a LILRB1 hinge.
However, Applicant discloses relevant figures, particularly figure 4, 22, 28, and 29, and example 5.
Firstly, Fig. 4 teaches that the engineered immune cells comprise activating and blocking receptors, and the level of the activating receptor decreases when the immune cells are in the presence of non-target cells (Paragraph [0456]). This figure shows the effect of the activating receptor in the presence of the non-target cell, but not the structure function relation that any and all activating receptors can exist with any and all blocking cells what happens when interacting with a tumor or non-tumor cell, or the use of LILRB1 as the hinge in the blocking receptor.
Fig. 22 shows the experimental results indicating that the blocking receptor provides a blocking signal that dominates and inhibits the activating signal from the activating receptor, wherein Jurkat cells were transfected with an activating receptor (MP1-CAR) for a MAGE-A3 activating ligand and a blocking receptor (ESO-Tmod) for a NY-ESO-1 blocking signal (Paragraph [0462]). This figure shows the structure function relationship between these pairs of activating and blocking receptors or ligands, but not the structure function relation that any and all receptors can exist with any and all ligands, the use of tumor cell, and the use of a LILRB1 hinge.
In fact, Applicant emphasizes that “the identity of the ligand binding domain (LBD) of the activating receptor drives the activity of the receptor.” (Paragraph [0144]). Specifically, in Fig. 26, different binding domains effect the receptors EC50, wherein LBD #1 has the highest EC50, and LBD # 2 – 3 have significantly lower EC50s. Similarly, the identity of the blocking receptor LBD can have large effects on the IC50 of the engineered immune cells (Paragraph [0210]). These figures show that there are specific ligand binding domains in both the activating and blocking receptors that impact the activity of the receptors. Thus, the results indicate a structure function relationship between specific ligand binding domains and the efficiency of the receptor, such that any and all receptors cannot exist with any and all ligands.
Applicant discloses relevant Figures, particularly Figures 28 and 29, and Figure 35. Figures 28 and 29 teach that the immune cells can have various combinations of TCRs (Paragraph [0234]). For example, Fig. 28 teaches a combination of a T cell with (i) an scFV activating receptor with a scFV blocker, (ii) an scFv activator with a Ftcr blocker, (iii) a TCR activator with a scFv blocker, and (iv) a TCR activator with a fTCR blocker. These figures only show the structure function relationship between these pairs of activating and blocking receptors, but not the structure function relation that any and all activating receptors can exist with any and all blocking cells can be used to produce an engineered immune cell that can bind to a tumor or non-tumor cell, the use of tumor or non-tumor cell, or the use of a LILRB1 hinge.
State of the art. Although the field of producing an engineered immune cell is highly
developed, the method of producing an engineered immune cell with engineered activating and blocking receptors, and using LILRB1 as a hinge in a receptor is not highly developed. The art must therefore be considered to be poorly developed.
Unpredictability of the art. Before the effective filing date of the claimed invention,
it was known in the art that scFv antibodies have poor stability, low solubility, and affinity, which seriously limits their clinical implication, as evidenced by Wang et al. (Wang R. et al. Engineering production of functional scFv antibody in E. coli by co-expressing the molecule chaperone Skp. Front Cell Infect Microbiol. 2013 Nov 6;3:72. PMID: 24224158; PMCID: PMC3818579.) (Abstract). The instant application recites the use of the scFV receptors, however, these receptors are shown to have poor stability, low solubility, and affinity, making them less effective candidates for cell surface receptors.
Further, by introducing a TCR into a T cell, there is decreased expression of the introduced and endogenous TCR, and the introduced and endogenous TCRs can form TCR dimers which can be neoreactive and leads to off-target effects, as evidenced by van Loenen et al. (van Loenen MM. et al. Mixed T cell receptor dimers harbor potentially harmful neoreactivity. Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10972-7. Epub 2010 Jun 1. PMID: 20534461; PMCID: PMC2890759.) (Abstract). The instant application recites the use of the engineering TCRs in the immune cell, however, when a TCR is introduced into a cell, there can be off-target effects and the formation of neo-reactive dimers.
Additionally, it was known that NK cells express a variety of activating and inhibitory receptors, but NK cells must remain tolerant of healthy tissue, and some of these receptors can also prevent activation of NK cells, as evidenced by Pegram et al. (Pegram HJ. Et al. Activating and inhibitory receptors of natural killer cells. Immunol Cell Biol. 2011 Feb;89(2):216-24. Epub 2010 Jun 22. PMID: 20567250.) (Abstract). Additionally, receptor families contain both “activating receptors” and “blocking receptors,” which can lead to inappropriate NK cell activation and decreased ability of the NK cells to discriminate normal, healthy tissue from infected or malignant tissue (pg. 217, right column, first paragraph).
Thus, the references indicate that there is a lot of unpredictability in the art pertaining to the specific types of receptors that are used in the engineered immune cells, including off-target effects, low expression levels, and inappropriate cell activation.
Additionally, it is known in the art that the D1D2 hinge domain of LILRB1 is involved in the recognition of MHC class 1 proteins, and it is the D1D2 hinge region is used to form the components of the ligand binding site and regulating immune tolerance, as evidenced by Cheng et al. (Cheng H. et al. Crystal structure of leukocyte Ig-like receptor LILRB4 (ILT3/LIR-5/CD85k): a myeloid inhibitory receptor involved in immune tolerance. J Biol Chem. 2011 May 20;286(20):18013-25. doi: 10.1074/jbc.M111.221028. Epub 2011 Mar 30. PMID: 21454581; PMCID: PMC3093875.) (pg. 18014, right column, second paragraph).
Further, there are 6 different isoforms of human LILRB1, as evidenced by Maute et al. (US 20180251558 A1, published 6 September, 2018) (Paragraph [0068]). Further, when LILRB1 is activated, the receptor transduces a negative signal that inhibits stimulation of an immune response in the cells on which it is expressed (Paragraph [0067]).
The applicant is on record for saying that Maute does not suggest that these compounds include the LILRB1 hinge, and that Maute discusses specific hinge embodiments (Applicant Remarks, pg. 11, last paragraph). Further, the applicant is on record for saying that the hinges made using LILRB1 derived peptides provide a pronounced and controllable effect on the strength of the receptor’s blocking signal (Applicant Remarks, pg. 10, first paragraph). However, it is still unclear what the exact sequence of the LILRB1 hinge sequence is, and its use in blocking receptors.
These two references (Cheng et al. and Maute et al.) show the variability in the human LILRB1 sequences, and the importance of only the specific D1D2 domain that is being used as a ligand binding site and regulating immune tolerance.
Amount of Experimentation Required. Given the unpredictability of the art, the
poorly developed state of the art with regard to the activating receptors and blocking receptors, wherein all activating receptors are compatible with all blocking receptors, and the variability in the LILRB1 sequences and the increased importance of certain components of the LILRB1 sequence, the skilled artisan would have to conduct undue, and unpredictable experimentation to practice the claimed invention using the engineered immune cells with the activating and blocking receptor, and using the LILRB1 as a hinge on the blocking receptor. Further, due to the lack of specific guidance in the specification for producing the engineered immune cell, it would require undue experimentation to practice the breadth of the instant methods as claimed.
Conclusion
Claims 1 – 3, 5 – 7, and 9 - 10 remain rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VYOMA SHUBHAM TIWARI whose telephone number is (571)272-2954. The examiner can normally be reached M-F 8:30 - 5:30 EST.
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/VYOMA SHUBHAM TIWARI/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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