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
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 August 11, 2025. Claims 1 – 21 are currently pending. Claims 1, 6, and 13 have been amended in the Applicant’s amendment filed August 11, 2025. No claims have been canceled or added in the Applicant’s amendment filed August 11, 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Claims 14 - 21 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claim 3, 4,7, 8-11were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.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. 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. The claims will be examined insofar as they read on the elected species.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 6 May, 2022 has been considered. An initialed copy of the IDS accompanies this Office Action.
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 (b)
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.
Claim 1 has been amended to recite “a peptide derived from leukocyte immunoglobulin-like receptor subfamily B member 1” . Claim 1 is vague and indefinite because it recites the phrase "derived from" and the metes and bounds of how a hinge can be "derived from" the claimed LILRBl and still meet the intended limitation of the claims are not clear. Without a clear statement of the process by which the starting material is derivatized, it is not possible to know the metes and bounds of a "derivative" because any given starting material can have many divergent derivatives depending on the process of derivatization, especially since the claimed starting material encompasses different versions of the LILRB derived hinges (See page 9 of Applicants’ remarks “Tmod2B I hinge is an LILRB I derived hinge. Similarly, the 2B I trunc (Tmod2B I truncated) is a shortened version of this LILRB I hinge. In FIG. 25, it is clear that the LILRB I derived hinges, produce a large and effective blocking signal, even when in a shorted form.” This rejection could be overcome by substituting "isolated" for "derived" in the claim.
For the purpose of a compact prosecution the term “derived” recited in claim 1 has been interpreted as “obtained or isolated from.”
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. This is a modified rejection necessitated by the amendment made to the claims filed 11 August, 2025.
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 derived from 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. 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 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 derived from LILRB1.
The instant claims encompass a genus of engineered cells with the contemplated use of killing tumor cells (lacking blocking ligand) but spare healthy cells (having both ligands) in the treating of cancer. There is not 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, wherein the spacer maintains an average minimum distance of about 100 to 1000 angstroms between the cell surface activating receptor and the cell surface blocking receptor and the cell surface blocking receptor that are capable of “elicits a cytotoxic response from the cell, thereby killing the tumor cell. Concurrently, the cell is able to preserve non-tumor cells, which express a second ligand that is not expressed by the tumor cell.” (see page 8 of Applicants’ remarks, para 2) thereby treating cancer.
Applicant only teaches Figure 35, where the inventors contemplate three 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 prophetically show the structure 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 claimed average minimum distance of about 100 to 1000 angstroms between the cell surface activating receptor and the cell surface blocking receptor. There is not disclosure of how these three contemplated examples on engineered immune cells of Fig 35 are able to “elicits a cytotoxic response from the cell, thereby killing the tumor cell. Concurrently, the cell is able to preserve non-tumor cells, which express a second ligand that is not expressed by the tumor cell.” (page 8 of Applicants’ remarks, para 2) In relation to the claimed spacer 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, 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. In fact, the Specification provides a single example were engineered cells were generated with five different activating receptors, i.e. CT479, CT482, CT486, CT487; CT488 (e.g., monoclonal antibodies) , each targeted the same activating ligand, epidermal growth factor receptor (EGFR), and the same blocking receptor.
PNG
media_image1.png
228
628
media_image1.png
Greyscale
The Specification states “Addition of the blocker caused some of the immune cells, like CT486-containing cells, to decrease their ability to kill target cells.” (para [0210]; FIGS. 33-34). The Specification is silent about any other combination of 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
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.
The Specification does not provide a single example of the claimed spacer 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, wherein immune cells comprising said genus of engineered immune cells comprising a cell surface activating receptor, a cell surface blocking receptor, and a spacer are able to “elicits a cytotoxic response from the cell, thereby killing the tumor cell. Concurrently, the cell is able to preserve non-tumor cells, which express a second ligand that is not expressed by the tumor cell.” (page 8 of Applicants’ remarks, para 2), thereby treating cancer.
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.
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 11 August, 2025 have been fully considered but they are not persuasive. Applicant essentially asserts (a) the present application discloses data showing immune cell, expressing activating and blocking receptors (pg. 8 – 11).
Regarding (a), the examiner acknowledges that amended claims and the as-Filed Specification teaches the immune cell expressing the activating and blocking receptors, wherein the blocking receptor comprises a hinge derived from LILRB1.
However, the rejection has been amended in response to the claims’ amendment filed on 8/11/2025 to address the lack of structure/ function correlation for the claimed genus of engineered immune cells comprising a cell surface activating receptor and a cell surface blocking receptor linked by a spacer able to maintain an average minimum distance of about 100 to 1000 angstroms between the cell surface activating receptor and the cell surface blocking receptor so as to control of receptor proximity and to modulate how immune cells can kill cancer cells but not harm healthy cells, even when both types of cells express similar antigens. As the structure of the spacer that is operably linked to the activating and blocking receptor cannot be determined from the claims and the as-Filed Specification, and the prior art is unpredictable in relation to using protein linkers or by engineering their physical/chemical properties as noted above, one of ordinary skill in the art won’t be able to determine what is the structure that maintains an average minimum distance of 100 to 1000 angstroms between the cell surface activating receptor and cell surface blocking receptor in the claimed genus of engineered immune cells . Therefore, the specification does not describe the claimed spacers maintaining an average minimum distance of about 100 to 1000 angstroms between the cell surface activating receptor and the cell surface blocking receptor a in such full, clear, concise and exact terms so as to indicate that Applicant has possession of these spacers at the time of filing the present application. Thus, the written description requirement has not been satisfied.
Conclusion
Claims 1, 2, 5, 6, and 12 - 13 remain rejected.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of
the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/VYOMA SHUBHAM TIWARI/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634