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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on Jun 22, 2026 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on June 22, 2026. Claims 1 – 21 are currently pending. Claims 1, 14, 18, and 20 have been amended in the Applicant’s amendment filed June 22, 2025. No claims have been canceled or added in the Applicant’s amendment filed June 22, 2025.
Applicant's election, in the reply filed 14 April, 2025 of Group I, claims 1 - 13, directed to engineered immune cell; and the following election of Species is acknowledged:
Species (A), (C ): the spacer comprises a rigid peptide linker (Claim 12), and
Species (B): the spacer comprises two moieties fused to the cell surface activating receptor (claim 6).
Claims 14 - 21 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claim 3- 4,7- 11 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.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 deemed proper and was therefore made FINAL.
The claims will be examined insofar as they read on the elected species.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election of invention has been treated as an election without traverse (MPEP § 818.03(a)).
Therefore, claims 1, 2, 5, 6, and 12 - 13 are under consideration to which the following grounds of rejection are applicable.
Priority,
The present application 21 September, 2021, claims the benefit of Provisional Applications 63/081,256, 63/081,258, 63/081,237, 63/081,248, 63/081,231, 63/081,242, 63/081,229, 63/081,250, all filed on 21 September, 2020.
Therefore, the earliest priority date is 21 September, 2020.
Maintained Objections/Rejections
Claim Rejections - 35 USC § 112
The rejection of claims 1, 2, 5, 6, and 12 - 13 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 applicant regards as the invention.
Claim 1 is indefinite for the recitation of “a spacer operably associated with the cell surface activating receptor” in line 4. It is unclear what is meant by “operably associated,” wherein is the spacer linked to the activating and blocking receptors or it is linked with another compound that can control the spacing. Thus, the metes and bounds of the claim cannot be determined.
Claims 2, 5, 6, and 12 - 13 are indefinite insofar as they ultimately depend from claim 1.
Claim Rejections - 35 USC § 112(a) - Written Description
The rejection of claims 1, 2, 5, 6, and 12- 13 is maintained 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, 2, 5, 6, and 12 - 13 encompass an engineered immune cell, comprising a cell surface activating receptor, a cell surface blocking receptor, and a spacer operably associated with the cell surface activating receptor and cell surface blocking receptor, wherein the spacer is configured to maintain the average minimum distance of about 100 to 1000 angstroms between the cell surface activating receptor and the cell surface blocking receptor on the immune cell surface, and the blocking receptors comprise a hinge, which has been obtained from the amino acid sequence of a hinge domain of LILRB1. 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 such that the activating receptor triggers a cytotoxic signal that promotes a cytotoxic response of the engineered immune cell when the activating receptor binds a first ligand of a target cell; and the blocking receptor sends an interfering signal that inhibits the cytotoxic response of the engineered immune cell when the blocking receptor binds a second ligand of the target cell (see withdrawn claim 14). Hence, the analysis below demonstrates that Applicant has not determined the core structure and correlation with the claimed function for full scope of the claimed product.
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 comprising a cell surface activating receptor, a cell surface blocking receptor, and a spacer operably associated with the cell surface activating receptor and cell surface blocking receptor, wherein the spacer is configured to maintain the average minimum distance of about 100 to 1000 angstroms between the cell surface activating receptor and the cell surface blocking receptor on the immune cell surface, and the blocking receptors comprise a hinge, which has been obtained from the hinge of LILRB1 and wherein the engineered immune cell with “blocking receptors including such a hinge are able to reversibly, and effectively prevent the cytotoxic response promoted by the activating receptors” (see page 8 of applicants’ remarks filed on 6/22/2026) .
The instant claims encompass a genus of engineered cells with the contemplated use of treating cancer wherein “immune cells, expressing the activating and blocking receptors, used in cell killing assays with respect to target cells expressing ligands targeted by the activating and/or blocking receptors) (page 9, last para of Applicant’s remarks filed on 6/22/2026). There is not a structure/function correlation for the claimed genus of engineered immune cells. In the instant case, Applicant does not disclose any relevant examples that teach the genus of engineered immune cells comprising a cell surface activating receptor, a cell surface blocking receptor, and a spacer operably associated with the cell surface activating receptor and the cell surface blocking receptor that exhibit the ability to inhibit activating receptor activation using the recited blocking receptor (page 9, last para of Applicant’s remarks filed on 6/22/2026) and thus treating cancer.
However, Applicant only teaches Figure 35, wherein the inventors have designed several strategies to ensure that the activating and blocking receptors are spaced at a distance to ensure a highly blocking signal strength (Paragraph [0217]). Particularly, Figure 35 teaches a C-terminal or N-terminal fusion bridge between the activator and blocker, or changing complementarity to enhance co-segregation. These figures only show the structure function relation of these particular spacers in regard to the engineered immune cell, but it does not teach maintaining the minimum required distance on the immune cell surface or the structure function relationship between the spacer and the activating and blocking receptors.
The as-Filed Specification teaches
“The spacer may covalently or non-covalently link the receptors such that the receptors are separated by a known spacing. The spacer may comprise a C- or N-terminal fusion. The receptors may be linked to the spacer via the LBD or ICD of each receptor. The receptors may be linked to the spacer at their respective hinge. The spacer may comprise one or more moieties that allow non-covalent binding of the receptors at their respective hinge. The spacer may comprise, for example, two moieties that are independently fused to the LBD, ICD, or hinge of each receptor. The receptors may be linked via a spacer that comprises a non-covalent interacting motif that mediates protein-protein interaction, such as leucine zipper. The receptors may be covalently attached via the spacer, and the spacer may comprise a cleavable linker such as a disulfide linker (Paragraph [0118]).”
Thus, it is unclear what exactly the spacer is made of, and how it is operably linked to the cell surface activating receptor and cell surface blocking receptor.
Before the effective filing date of the claimed invention, it was known in the art that cross linkers have long and flexible spacers for linking two protein components. Because of this, the relative orientation and distance between their two components is largely unpredictable, as evidenced by Jeong et al. (Jeong WH. Et al Connecting two proteins using a fusion alpha helix stabilized by a chemical cross linker. Nat Commun. 2016 Mar 16;7:11031. doi: 10.1038/ncomms11031. PMID: 26980593; PMCID: PMC4799363.) (pg. 2, left column, first paragraph). Thus, a fusion α helix formed by joining two pre-existing helices into a single extended helix was used to connect the proteins (Abstract).
Further, it was known in the art that the average spacer length should be equal or slightly smaller than the distance between the receptor binding pockets and that the end-to-end spacer length fluctuations should be in the same range as the size of a receptor binding pocket, as evidenced by Liese and Netz. (Liese S, Netz RR. Influence of length and flexibility of spacers on the binding affinity of divalent ligands. Beilstein J Org Chem. 2015 May 15;11:804-16. doi: 10.3762/bjoc.11.90. PMID: 26124882; PMCID: PMC4464470.) (Abstract). (Please note: The receptor has two binding pockets with a distance d from each other and a binding range σ.). Thus, there is a specific formula for determining the spacer length between the receptors.
Additionally, it was known that the length and structure of the linkers can also control the distance between functional domains and affect the stability of the fusion protein, as evidenced by Chen et al. (Chen X. et al Fusion protein linkers: property, design and functionality. Adv Drug Deliv Rev. 2013 Oct;65(10):1357-69. doi: 10.1016/j.addr.2012.09.039. Epub 2012 Sep 29. PMID: 23026637; PMCID: PMC3726540.) (pg. 9, first full paragraph). The structure is imperative to the controlling the distance between the functional domains of the proteins.
Thus, the ability to assess a priori whether any and all types of spacers can exist between the activating and blocking receptors, and the structure of these spacers is not predictable.
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 method of culturing natural killer cells as recited in the instant claims. The disclosure is broad and vague and does not define any particular engineered immune cell that would facilitate the claimed effect of method of treating cancer where “the cell surface blocking receptor is prevented from sending a cytotoxic signal due to the spacer maintaining the cell surface blocking receptor at least the average minimum distance on the immune cell surface from the cell surface activating receptor, and wherein said blocking receptor comprises a hinge, wherein said hinge comprises a peptide with an amino acid sequence obtained from a hinge domain of LILRB 1” (Withdrawn - Currently Amended claim 14)).
Response to Arguments as they apply to rejection of claims 1, 2, 5, 6, and 12- 13 under 35 USC § 112(a) - Written Description
Applicant’s arguments filed June 22, 2026 have been fully considered but they are not persuasive. Applicant essentially asserts (a) the specification teaches that the engineered immune cells with blocking receptors including such a hinge are able to reversibly, and effectively prevent the cytotoxic response promoted by the activating receptor (pg. 8 fourth paragraph); (b) the specification teaches that LILRB1 derived produce a large and effective blocking signal, even when it is in a shortened form (pg. 9, first paragraph); and (c) the application explains that the control of crosstalk can be modified by altering the spacing between the receptors, for which specific structure are provided (pg. 10, full page).
Regarding (a), Applicant is reminded that the instant claims are directed to a product, and not a method. Additionally, the applicant discusses the details of the specification, which teaches that the engineered immune cells are able to reversibly and effectively prevent the cytotoxic response promoted from the activating receptor. Further, the disclosure does not define a particular engineered immune cell that where the “the cell surface blocking receptor is prevented from sending a cytotoxic signal due to the spacer maintaining the cell surface blocking receptor at least the average minimum distance on the immune cell surface from the cell surface activating receptor, and wherein said blocking receptor comprises a hinge, wherein said hinge comprises a peptide with an amino acid sequence obtained from a hinge domain of LILRB 1. The applicant notes that the LILRB1 hinge provides effective, ligand-dependent blocking, without hindering the activation signal (Applicant Remarks, pg. 8, last paragraph). However, this teaching does not clarify whether the engineered immune cells are capable of killing cells as a method of treating cancer, and it does not clarify which activation signals are being activated on the cells.
Regarding (b), the Applicant notes that the application provides experimental results validating the recited LILRB1 hinge, wherein the LILRB1 hinges produce a large and effective blocking signal (pg. 9). In the as-Filed Specification cites Fig. 25, which shows that lengthening a hinge from 25 amino acids to 35 amino acids confers a significant increase in blocker strength, and the increase becomes more dramatic as the hinge length approaches 65 amino acids in length (As filed Specification, pg. 35, lines 17 – 18). Fig. 25 does teach that the hinge of LILRB1 (referred to as “2B1” has been tested. The instantly amended claim teaches that the hinge comprises an amino acid sequence obtained from a hinge of LILRB1. Fig. 25 teaches a variety of different hinges that were tested, but does not teach the effect of varying the sequence of these hinges to yield the same result. As such, there is no way of knowing exactly which amino acids of the hinge of LILRB1 can be used in an engineered immune cell to confer blocker strength. Furthermore, there is no evidence that engineered cells comprising the various hinge sizes of Fig 25 in the context of the engineered cells comprising a cell surface activating receptor and a cell surface blocking receptor are capable of inhibit activating receptor activation using the recited blocking receptor so as to treat cancer.
Regarding (c), Applicant argues that the application explains that the control of crosstalk can be modified by altering the spacing between the receptors, for which specific structure are provided. However, this argument is not found persuasive. The applicant cites Paragraph [0014] and [0015] of the as-Filed Specification, such that the applicant argues that the specific structures of the spacers are provided. However, these paragraphs do not explicitly teach the spacers that between the cell surface activating and blocking receptor. Specifically, these paragraphs do not teach the minimum distance of 100 to 1000 angstroms between the activating and blocking receptors, as required by claim 1.
Further, the applicant notes figs. 33 and 34 to “show the impact of receptor cross-talk can have on the ability of the blocking receptor to inhibit the activation signal.” Specifically, the as-Filed Specification teaches that the as the distance between a blocking receptor and activating receptor decreases, the impact of this cross-talk increases (Paragraph 0015]). However, these figures do not detail what is the distance between the activating and blocking receptor.
Additionally, regarding these figures, the disclosure teaches that the “engineered immune cells were created with one of five different activating receptors, targeting the same activating ligand (EGFR) (Paragraph [0467]). Thus, it can only be concluded that the engineered immune receptors have the ability to kill target cells that express the specific activating ligand – EGFR. In sum, the instant specification does not provide any guidance that would steer the skilled practitioner toward engineered immune cells that express activating and blocking receptors that can be used to carry out the claimed methods -- an essential element of every claim of the application -- and has not provided evidence that any such activating and blocking receptors were otherwise within the knowledge of a person of ordinary skill in the art at the relevant time. The disclosure is limited to the examples specified above and does not define any particular activating and blocking receptors that would facilitate the claimed effect of the methods of inhibit activating receptor activation using the recited blocking receptor so as to treat cancer.
Conclusion
Claims 1, 2, 5, 6, and 12 - 13 remain rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VYOMA SHAILESH THAKKER 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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