DETAILED ACTION
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 .
Claim Status
Applicant’s reply filed on 12/11/2025 is acknowledged. Claims 6, 11, 13, 16, 46, 48, and 49 have been amended. Claims 7-8, 12, 14, 36-45, 47 and 50 are cancelled.
Claims 6, 9-11, 13, 16, 46, 48-49 and 51-65 are pending and under examination.
Objections Withdrawn
The objection of claims 7 and 8 is withdrawn in view of cancellation of claims in the amendments filed 12/11/2025.
Rejections Maintained
Claim Rejections - 35 USC § 112(a)
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.
WRITTEN DESCRIPTION
Claims 6, 9-11, 13, 16, 46, 48-49, 51-53 and newly added claims 54-65 remain/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 claims contain 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, 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 claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
The teachings of the specification and the claimed invention
Claims 6 and 54 are directed to a method of selecting a T cell line from a collection of T cell lines for therapeutic administration to a human patient to treat a disease or disorder associated with a pathogen or to treat a cancer in the human patient. The independent claim does not disclose the source of the collection of T cell lines.
The specification provides the following teachings relevant to the claimed methods:
The “collection of T cell lines” in the examples of the instant disclosure are EBV-CTLs derived from a bank of 330 EBV-CTL lines generated from leukocytes donated from hematopoietic cell donors (Specification, Pg. 78, 6.5.5 Generation and characterization of EBV-CTL Lines).
The state of the relevant art
The state of the relevant art teaches important considerations pertaining to the generation and selection of T cells for therapeutic administration.
Pudney (J Exp Med. 2005 Feb 7;201(3):349-60.) investigated the hierarchy of immunodominance among EBV antigens expressed during viral infection. Pudney determined a correlation between hierarchy of immunodominance among EBV lytic cycle antigens for CD8+ T cell responses and the efficiency with which the antigens are processed and presented to CD8+ T cells in lytically infected cells (Pg. 357, Left column, Full paragraph 1, Lines 1-5). This hierarchy of immunodominance of EBV antigens indicates not all T cell lines, even if they are antigen specific are effective at treating EBV-related diseases.
Pertaining to the generation of T cell lines suited for therapeutic administration for the treatment of EBV-associated diseases, O’Reilly 2011 (Best Pract Res Clin Haematol. 2011 Sep;24(3):381-91, IDS 12/30/2020) details a ten-year process of generating a large bank of GMP EBV-specific T cells derived from bone marrow transplant donors that had been sensitized in vitro for periods of 28–35 days with irradiated, acyclovir treated autologous EBV transformed B cells (Pg. 6, Full paragraph 2, Lines 1-4). O’Reilly teaches the use of the partially matched third-party T cells selected on the basis of partial HLA matching and restriction to the patient for the treatment of EBV lymphoma (Pg. 6, Full paragraph 3, Lines 1-9).
O’Reilly 2016 (Bone Marrow Transplant. 2016 Sep;51(9):1163-72, IDS 12/30/2020) teaches only a small number of centers have established cryopreserved banks of varying size containing EBV-specific GMP grade T cell lines with characterized virus-specificity and HLA type (Pg. 10, Fill paragraph 2, Lines 1-4). Pertaining to the Memorial Sloan Kettering Cancer Center of the instant disclosure, O’Reilly further teaches about the bank of over 300 EBV-specific T cell lines which are able to provide appropriately HLA restricted EBV-specific T cell that are matched with a patient for at least two alleles for over 98% percent of patients referred to their center for treatment (Pg. 12, Full paragraph 1, Lines 1-6). All EBV-specific T-cells were HLA typed at high resolution and characterized as to virus specificity and HLA restriction. The T-cell lines were characterized as to their peptide epitope specificities (Pg. 11, Full paragraph 1, Lines 1-8).
Vickers (Br J Haematol. 2014 Nov;167(3):402-10, IDS 12/30/2020) describes in detail the establishment of the bank of EBV-specific CTLs at the Scottish National Blood Transfusion Service, teaching the years-long process beginning with donations of PBMC that were screened to be EBV-positive, negative for other diseases, and selected to maximize the probability of HLA class I and class II matches (Pg. 403, Right column, Full paragraph 1, Lines 1-14). The process included demonstrating functionality of CTLs through killing and specificity for target cells and generation of cell lines according to compliance with GMP (Pg. 404. Right column, Lines 8-13). In all, the art teaches the lengthy and arduous process in producing a collection of cell lines that are antigen specific and verified as clinically relevant for therapeutic treatment of disease.
Importantly, a key component of selecting T cell lines for treatment from an already established T cell collection is that the EBV-CTL restriction needs to correspond to the HLA expressed on the infected cells in order to eradicate disease. Barker (Blood. 2010 Dec 2;116(23):5045-9, IDS 12/30/2020) teaches treatment of a patient with EBV-specific T cells generated from the third-party donor restricted by the B*0801 and C*0701 HLA-alleles presented on the EBV+ tumor of the patient (Fig. 1A). The patient EBV viremia resolved completely after EBV-specific T-cell administration with partial clinical remission after 3 infusions and complete remission after 5 infusions (Fig. 1A). Barker concludes that the approach demonstrates the efficacy of using “off-the-shelf” virus-specific third party CTLs restricted by HLA expressed by the tumor (Abstract, far right column).
To this end, WO2016/073550 (IDS 12/30/2020) teaches choosing an allogeneic T cell line restricted to an HLA allele or HLA allele combination known to have high relative activity and expressed in the patient or diseased cells of the patient (Pg. 18, [0065], Lines 3-9). The reference teaches “Adoptively transferred virus-specific T-cells, to be effective, must be specific for a viral peptide epitope that is both expressed by host cells infected by the virus and presented by an HLA allele expressed by the infected host cells and the donor T-cells through which the HLA-restricted (Pg. 46, [00160]). Thus, the art teaches that the “entity” to which T cell lines restriction should be determined is based on the origin of the infected tissue. Selecting T cells restricted to HLA of an “entity” that is not the source of diseased cells would not have therapeutic efficacy.
Claim analysis
Based on the teachings of the specification and the state of the relevant art, the claims have the following written description issues:
The claims disclose a “collection of T cell lines” while the specification and relevant art teach that not all collections of T cell lines are suited for treatment of such a broad range of diseases even if they are specific to antigens of the pathogen or cancer. The art and the instant specification disclose a specific collection of EBV-specific T cells carefully curated over a decade that are representative of HLA alleles matched to the majority of the population, that are antigen-specific and HLA restricted to immunodominant EBV antigens, produced under good manufacturing practices and vetted as safe and effective in clinical studies. In the instant disclosure, the inventors have shown possession of a collection of EBV-CTLs, but this cell line is not representative of the breadth of the claims.
Therefore, the inventors were not in possession of the claimed invention as broadly claimed and the disclosure does not provide sufficient guidance and detail for a person skilled in the field to carry out the invention based on the disclosure provided.
Claims 9-11, 13, 16, 46, 48-49, 51-53, and 55-65 are rejected under 35 U.S.C. 112(a) for being dependent on claim 6 not providing limitations that satisfy the written description requirement.
Response to Applicant’s Arguments
Applicant's arguments filed 12/11/2025 have been fully considered but they are not persuasive.
The applicant traverses the written description on the grounds that they have narrowed the specificity of the “disease or disorder” to EBV-PTLD pose HSCT or post-SOT and have added an “entity” selection method that has a reasonable likelihood of selecting T cell lines restricted to HLA alleles shared with the diseased cells (Remarks, Pg. 10-11).
In response, the arguments pertaining to the “collection of T cells” are still pending. In view of the instant disclosure and various non-patent literature from the instant inventors, it is clear that the term “collection of T cells” in claims 6 and 54 refers only to a specific few collections of T cells in the possession of the instant inventors and their collaborators. The T cell collections are donor-derived CD8+ EBV-specific T cell banks curated at the centers associated with the applicants. While the amendment introduces the limitation “against one or more antigens of EBV” this does not resolve the issue of the nature of the collection of T cell lines. The claims are broadly directed to any collection of T cell lines.
ENABLEMENT
Claims 6, 9-11, 13, 16, 46, 48-49, 51-53 and newly added 54-65 remain/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 enablement requirement. The claim(s) contains 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.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and nature of the invention
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed method is that:
Any collection of T cell lines can be used as a starting material for the selection process and subsequent treatment method (claim 6),
Any 4 HLA loci of the entity can be ascertained and that information would be sufficient to inform HLA restriction decisions independent of the HLA-restrictions represented in the T cell line (claim 9), and
Because of the inherent difficulty of developing “off-the-shelf” adoptive cellular therapy methods and the broad nature of the claims, a skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification.
The state of the prior art and level of predictability in the art
As detailed in the state of the relevant art section of the written description rejection above, the art teaches the rigorous nature of establishing “off-the-shelf” collection of T cell lines suitable for the claimed methods. The art is highly unpredictable due in part to the hierarchy of immunodominant antigens specific to each pathogen or cancer and the HLA polymorphisms in the human population.
The art at the time of filing provided enabling guidance for treating EBV-related infections and cancers using cells selected from the specific EBV-CTL bank developed by the inventors and potentially using cells from EBV-specific banks established by a small number of other research entities with curated cell collections (see O’Reilly 2016, supra).
Importantly, the art teaches adoptive T cell therapy is effective when the T cell lines are restricted to the HLA of the diseased cells (see Barker, supra). The origin of the tumor or diseased cells could be either the transplant donor or the patient, but the cell must match the “entity” from which the disease originates.
The amount of direction provided by the inventor and the existence of working examples
What is enabled by the working examples is narrow in comparison to the breadth of the claims: The specification discloses the use of EBV-CTL lines selected from a third-party, allogeneic, off-the-shelf bank of 330 GMP EBV-CTL lines from specifically consented healthy donors for treating biopsy proven EBV associated lymphomas (Specification, Pg. 52, [001490]).
The specification does not disclose any other working examples that would provide enabling support for use of the claimed method.
The quantity of experimentation needed to make or use the invention
The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is treatment of a patient with pathogen-associated disease or a cancer using adoptive T cell therapy, a person having ordinary skill in the art would have to perform multiple further in vivo experiments in human clinical trials that are predictive of the generation of T cell lines and the treatment of human patients. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating prostate cancer. Therefore, claims 6, 54 and dependent claims are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Response to Applicant’s Arguments
Applicant's arguments filed 12/11/2025 have been fully considered but they are not persuasive.
The applicant argues the claims as currently written provide enablement for the claimed method in view of the state of the art that teaches multiple groups reporting the use of EBV-specific T cells to treat EBV-PTLD (Remarks, Pg. 14).
In response, the claims as currently amended still require undue further experimentation. A person could not readily recapitulate this process if they were not in possession of the claimed “collection of T cell lines” or an equivalent collection of third party, allogeneic EBV-specific T cells. As written, the method indicates that any collection of T cells could be used for the selection of therapeutic T cells for the treatment of EBV-PTLD. One cannot envision how someone not in possession of these specific donor-derived EBV+ T cell lines of the disclosure could perform this method. Each of the references cited in the remarks Pg. 14 disclose the characteristics and origin of the cells used in their studies and the cells used were commensurate with their disclosed therapies.
For example, O’Reilly 2016 (Bone Marrow Transplant. 2016 Sep;51(9):1163-72, IDS 12/30/2020) teaches a bank of over 300 EBV-specific T cell lines which are able to provide appropriately HLA restricted EBV-specific T cell that are matched with a patient for at least two alleles for over 98% percent of patients referred to their center for treatment (Pg. 12, Full paragraph 1, Lines 1-6). All EBV-specific T-cells were HLA typed at high resolution and characterized as to virus specificity and HLA restriction. The T-cell lines were characterized as to their peptide epitope specificities (Pg. 11, Full paragraph 1, Lines 1-8).
The use of term “a collection of T cells” does not provide any information regarding the T cell composition including the types of T cells (cytotoxic, Th1, Th2, Th17, Treg, etc.), the epitopes represented in the cell lines, or the HLA allele restrictions of the cell lines. For this reason, the method as presently claimed is not enabled.
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.
Claims 6, 9-11, 13, 16, 46, 48-49, 51-53 and newly added claims 54-65 remain/are rejected under 35 U.S.C. 103 as being unpatentable over O'Reilly (WO 2016/073550 A1, published 05/12/2016, IDS 12/30/2020) in view of Barker (Blood. 2010 Dec 2;116(23):5045-9).
The disclosure of O’Reilly is directed to methods of selecting an allogeneic T cell line for therapeutic administration to a patient having a pathogen or cancer (Abstract). The disclosure differs from the instant methods in that the instant invention requires the use of cell lines restricted to greater than one HLA allele.
Regarding claims 6 and newly added 54, pertaining to a method of selecting a cell line from among a collection of T cell lines for therapeutic administration to a human patient to treat a disease or disorder associated with a pathogen or to treat a cancer in the human patient, wherein the human patient has been the recipient of a cellular transplant, O’Reilly teaches the following limitations:
A method of selecting an allogeneic T cell line for therapeutic administration to a human patient having a pathogen (Pg. 48, claim 1) wherein the patient has received a solid organ transplant (Pg. 56, claim 99) or an HSCT (Pg. 57, claim 103).
Selecting a T cell line allogeneic to the patient that recognizes at least one epitope of an antigen of the pathogen or cancer (Pg. 48, claim 1).
Identifying a plurality of HLA alleles and HLA allele combinations in the T cell lines (Pg. 48, claim 1) and ascertaining the HLA assignment for the T cell donor (Pg. 51, claim 37).
Selection process that comprises selecting cell lines with common HLA restriction with the patient or diseased cells (Pg. 48, claim 1(B)).
Regarding claims 9 and newly added 55, wherein the step of ascertaining the HLA assignment of the entity comprises typing at least 4 HLA loci, O’Reilly teaches a step prior to the selecting step a step of ascertaining the HLA assignment of the patient or of the diseased cells in the patient (Pg. 48, claim 4), wherein the step of ascertaining comprises typing at least 4 HLA (Pg. 49, claim 5).
Regarding claims 10-11 and newly added 56-57, wherein the selected T cell line is derived from a human donor that is allogeneic to the human patient (claim 10) and wherein the human donor is a third-party donor that is different from the donor of the cellular transplant (claim 11), O’Reilly teaches the T cell line is allogeneic (Pg. 48, claim 1) and teaches the use of pre-generated third-party donor derived virus specific cell lines ([0010], Lines 1-12).
Regarding claims 13 and newly added 58, wherein the disease or disorder is an EBV-PTLD post SOT and the entity is the human patient, O’Reilly teaches the patient has undergone hematopoietic stem cell transplant (Pg. 50, claim 17) and that the cancer is an EBV-PTLD (Pg. 50, claim 29). O’Reilly teaches determining within the cell line the most active (highest ranked) HLA allele or alle combination in common with the patient or the diseased cell in the patient (Pg. 18, [0064], Lines 1-8). The instant specification teaches the diseased cell in the patient can originate from the cellular transplant donor (Specification, Pg. 25, [0066]).
Regarding claims 16 and newly added 59, wherein the disease or disorder or the cancer is an EBV-PTLD post SOT and the entity is the human patient, O’Reilly teaches T cell restricted to a plurality of alleles and selection of a T cell line that has HLA restriction in common with the patient (O’Reilly, claim 1) and the cancer is an EBV-PTLD (Pg. 50, claim 29).
Regarding claims 46, 48, 49 and newly added 60-62, pertaining to a method of treating a disease or disorder associated with a pathogen or treating a cancer in a human patient, wherein the disease or disorder or cancer is an EBV-associated post-transplant lymphoproliferative disorder, the method comprising selecting T cells according to methods addressed above and administering to a human patient, O’Reilly teaches a method of treating a human patient comprising selecting an allogeneic T cell line for therapeutic administration to the patient and administering the cell to the patient (Pgs. 56-57, claim 102).
Regarding claims 51-53 and newly added 63-65, wherein one or more steps of the method of claim 6 are carried out using a computer system (claim 51), wherein all the steps are carried out using a computer system (claim 52) and where the computer system comprises a central processing unit and memory for storing electronic instructions for performing one or more steps of the method (claim 53), O’Reilly teaches a computer system for selecting an allogeneic T cell line for therapeutic administration to a human patient having or suspected of having a pathogen or cancer, comprising a central processing unit, a memory coupled to the central processing unit for storing instructions for performing the selection steps (Pg.56, claims 100-101).
O’Reilly does not teach a method of excluding from the selected T cell lines the T cell lines that exhibit a T cell response against one or more antigens of the pathogen or cancer that are restricted by only one HLA allele shared with the entity.
This deficiency is taught by Barker.
The disclosure of Barker describes two cases of successful treatment of cord blood transplantation derived EBV-PTLD with partially HLA-matched third-party EBV-specific CTLs (Pg. 5045, Left column, Lines 8-11). Barker describes the treatment of “Patient #1” with EBV-CTLs restricted by B*0801 and C*0701 HLA-alleles presented on the EBV+ tumor of the patient (Fig. 1). Barker teaches that EBV viremia resolved completely after EBV-specific T-cell administration with partial clinical remission after 3 infusions and complete remission after 5 infusions (Fig. 1). “Patient #2” was treated with EBV-CTLs restricted by HLA-B*3501 corresponding to the lymphoma (Fig. 1). This resulted in partial remission after the 3 infusions (course 1), complete remission after 6 infusions (course 2) and required an additional course of infusions due to lingering symptoms, totaling 9 infusions total for sustained complete remission (Pg. 5047, Right column, Full paragraph 1). Though direct comparison between the two patients is not possible because they were treated by T cell lines restriction to different antigens/HLA, Barker’s disclosure clearly shows the efficacy of choosing therapeutic T cell lines based on restriction to HLA on the tumor cells, in particular the efficacy of restriction to more than one allele such as in the case of Patient #1.
It would have been obvious to one having ordinary skill to combine the teachings of O’Reilly and Barker to produce a method that excludes T cell lines restricted to only one HLA allele shared with the entity and thus require the selection of cell lines that are restricted to two or more HLA alleles in common with the entity expressing disease antigen. One would have been motivated to do so because both O’Reilly and Barker teach the prioritization of restriction of the cell lines to alleles from the diseased entity. Barker specifically teaches that administration of EBV-CTLs restricted to two HLA alleles on the EBV+ lymphoma produced sustained complete remission after 5 infusions. Thus, Barker teaches an intentional step of selecting EBV-CTLs restricted to more than one HLA on the diseased cells of a human patient and provides evidence of effectiveness in treating EBV-PTLD. There would be an expectation of success in combining to the teachings of Barker and O’Reilly to produce a method that requires restriction to more than one HLA allele to treat a patient because Barker teaches the efficacy of selecting T cell lines on the basis of HLA restriction to more than one HLA allele.
Response to Applicant’s Arguments
Applicant's arguments filed 12/1 have been fully considered but they are not persuasive.
The applicant traverses the rejection on the basis that neither O’Reilly or Barker discloses or suggests an affirmative step of excluding from selection for therapeutic administration of those T cell lines that are restricted to only one shared HLA allele (Remarks, Pg. 18). The applicant further asserts that neither O'Reilly nor Barker suggests that excluding T cell lines restricted to only one shared HLA allele would be therapeutically beneficial (Remarks, Pg. 18).
In response, the art teaches selection of cell lines restricted by at least one HLA allele in common with the diseased entity and the instant invention teaches selection of cell lines restricted by more than one HLA allele. In view of this, the issue of patentability over the art can be distilled down to whether it would be obvious to select for more than one matched allele restriction. The applicant argues that such a selection is not trivial because doing so greatly reduces the number of T cell lines available for therapeutic use. However, any degree of selection including the “at least one” as taught in the art restricts the available cells. Though selection methods are not trivial, it is absolutely necessary for prioritizing the therapeutic potential of the transferred cells in each individual patient. The applicant has failed to support the argument that one having ordinary skill in the art would not be motivated to select cell lines restricted to more alleles if said cell lines were available.
The applicant characterizes the examiner’s assertion that selection of cell lines restriction to more than one shared HLA allele would be more therapeutically efficacious than cell lines restricted to only one cell line as mere speculation. The art however, supports the use of cell lines restricted to more than one HLA allele matched to the patient for at least the following rationales known to those having ordinary skill in the art:
Administration of cell lines restricted to more than one HLA allele matched to the disease mitigates the limitations of hierarchy of immunodominance amongst EBV antigens and mutations that cause preferential presentation of subdominant and/or cryptic antigens. As described in the disclosure of Pudney above, there is a correlation between hierarchy of immunodominance among EBV lytic cycle antigens for CD8+ T cell responses and the efficiency with which the antigens are processed and presented to CD8+ T cells (Pg. 357, Left column, Full paragraph 1, Lines 1-5). This hierarchy of immunodominance of EBV antigens indicates not all T cell lines, even if they are antigen-specific and HLA-restricted are equally effective at treating EBV-related diseases. Selecting cell lines restricted to more than one HLA allele allows for recognition of multiple epitopes, allowing for therapeutic effect even if one epitope is subdominant or exhibits low antigen burden in the patient. Pertaining specifically to EBV, de Campos-Lima (J Exp Med. 1994 Apr 1;179(4):1297-305) teaches that EBV strains are known acquire mutations that abolish presentation of immunodominant target epitopes restricted to HLA A11-restricted CTL recognition in both a Papua New Guinea and Chinese population (Abstract). In light of the selective pressure for the presentation of subdominant antigens, administration of T cells lines that recognize multiple epitopes would be favored.
Administration of cell lines restricted to more than one HLA allele matched to the disease mitigates immune evasion strategies employed in EBV infections and other hematologic malignancies, most notably, HLA loss/downregulation as means of resistance to T cell recognition. Pagliuca et al. (Front Immunol. 2022 Sep 5;13:944872) teaches selective pressure leads to downregulation of antigen presentation machinery as means of evading immune surveillance in multiple malignancies; this downregulation or “HLA loss” can occur by genetic and epigenetic mechanisms directly affecting the HLA region or the genes encompassing degradation, transportation and processing (Pg. 06, Right column, Section 7 Somatic dysfunction of HLA diversity: HLA loss and beyond). To this end, it was known in the art prior to the filing date of the instant application that EBV can impair CD4+ and CD8+ T cell recognition by a strong HLA I and HLA II downmodulation (Merlo et al. Haematologica. 2010 Oct;95(10):1769-77, Pg. 1769, right column, lines 8-11). Again, administration of T cells lines that recognize multiple epitopes would be favored as compensatory mechanism for known immune evasion strategies.
In total, the applicant has failed to show how a selection process that favors cell lines that exhibit a T cell response to a greater number of HLA-restricted antigens matched to the disease would be not be obvious. For this reason, the 35 U.S.C. 103 rejection is maintained.
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 reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Patent No. 11,173,205
Claims 6, 9-11, 13, 16, 46, 48-49, 51-53 and newly added 54-65 remain/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,173,205 in view of Barker (Blood. 2010 Dec 2;116(23):5045-9 and O'Reilly (WO 2016/073550 A1, IDS 12/30/2020).
The disclosures of O’Reilly and Barker are discussed above and are incorporated herein.
Regarding instant claims 6, 10-11, 13, 16, and 46-49 and newly added 54, 56-62, pertaining to a method of selecting a cell line from among a collection of T cell lines for therapeutic administration to a human patient to treat a disease or disorder associated with a pathogen or to treat a cancer in the human patient, wherein the human patient has been the recipient of a cellular transplant, ‘205 teaches the following limitations:
A method of selecting an allogeneic T cell line for therapeutic administration to a human patient having a pathogen or cancer (‘205 claim 1), wherein the virus is EBV (‘205 claim 9), the cancer is EBV-PTLD (‘205 claim 13), and the antigen is EBV antigens EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C, LMP1 or LMP2 (‘205 claim 14).
Wherein the patient has undergone a hematopoietic stem cell transplant (‘205 claim 7).
Patent ‘205 does not teach (1) excluding from the T cell lines any T cells lines that are restricted by only one HLA allele shared with the entity, (2) that the step of ascertaining the HLA of the entity comprises typing at least 4 HLA loci, (3) that the patient’s cellular transplant is a solid organ transplant or (3) that the selection process is carried out using a computer system.
These deficiencies are taught by Barker and O’Reilly.
Regarding the limitation of instant claim 6 and newly added 54 wherein therapeutic T cell lines restricted to one or fewer HLA alleles in common with the entity, Barker teaches the successful treatment of a patient with EBV-PTLD with third-party EBV-CTLs restricted to two HLA alleles shared with the EBV+ diseased cells.
Regarding instant claim 9 and newly added 55, wherein the step of ascertaining the HLA assignment of the entity comprises typing at least 4 HLA loci (claim 9), O’Reilly teaches the step of ascertaining the HLA assignment of the patient or of the diseased cells in the patient comprises typing at least 4 HLA (Pg. 49, claim 5).
Regarding instant claims 51-53 and newly added 63-65, wherein one or more steps of the method of claim 6 are carried out using a computer system (claim 51), wherein all the steps are carried out using a computer system (claim 52) and where the computer system comprises a central processing unit and memory for storing electronic instructions for performing one or more steps of the method (claim 53), O’Reilly teaches a computer system for selecting an allogeneic T cell line for therapeutic administration to a human patient having or suspected of having a pathogen or cancer, comprising a central processing unit, a memory coupled to the central processing unit for storing instructions for performing the selection steps (Pg.56, claims 100-101).
It would have been obvious to one having ordinary skill to combine the teachings of ‘205 with the teachings of O’Reilly and Barker to produce the method of selecting T cell lines for therapeutic administration to a human patient. One would have been motivated to do so because ‘205 teaches selection of T cells based on known activity against pathogen and O’Reilly and Barker teach the prioritization of restriction of the cell lines to alleles from the diseased entity. Barker specifically teaches that administration of EBV-CTLs restricted to two HLA alleles on the EBV+ lymphoma produced sustained complete remission after 5 infusions. Thus, Barker teaches an intentional step of selecting EBV-CTLs restricted to more than one HLA on the diseased cells of a human patient and provides evidence of effectiveness in treating EBV-PTLD. There would be an expectation of success in combining to the teachings of ‘205, Barker and O’Reilly to produce a method that requires restriction to more than one HLA allele to treat a patient because Barker teaches the efficacy of selecting T cell lines on the basis of HLA restriction to more than one HLA allele.
Pat. No. 12,533,407 (previously rejected as Copending Application No. 17/497,439)
Claims 6, 9-11, 13, 16, 46, 48-49, 51-53 and newly added 54-65 remain/are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12,533,407 in view of Barker (Blood. 2010 Dec 2;116(23):5045-9 and O'Reilly (WO 2016/073550 A1, IDS 12/30/2020).
The disclosures of O’Reilly and Barker are discussed above and are incorporated herein.
Regarding instant claims 6, 10-11, 13, 16, and 46-49 and newly added 54, 56-62, pertaining to a method of selecting a cell line from among a collection of T cell lines for therapeutic administration to a human patient to treat a disease or disorder associated with a pathogen or to treat a cancer in the human patient, wherein the human patient has been the recipient of a cellular transplant, ‘439 teaches the following limitations:
A method of treating a human patient having a cancer that is an EBV-positive post-transplant lymphoproliferative disorder (‘407 claim 6)
The method of treating comprises selecting an allogeneic T cell line for therapeutic administration that recognizes at least one epitope of the pathogen or cancer the HLA allele or allele combination of the T cell line is restricted is known to be in common with the patient or diseased cells in the patient (‘407 claim 6).
Patent ‘407 does not teach (1) excluding from the T cell lines any T cells lines that are restricted by only one HLA allele shared with the entity, (2) that the step of ascertaining the HLA of the entity comprises typing at least 4 HLA loci, (3) that the patient’s cellular transplant is a hematopoietic stem cell transplant or a solid organ transplant or (3) that the selection process is carried out using a computer system.
These deficiencies are taught by Barker and O’Reilly.
Regarding the limitation of instant claim 6 and newly added 54 wherein therapeutic T cell lines restricted to one or fewer HLA alleles in common with the entity, Barker teaches the successful treatment of a patient with EBV-PTLD with third-party EBV-CTLs restricted to two HLA alleles shared with the EBV+ diseased cells.
Regarding instant claim 9 and newly added 55, wherein the step of ascertaining the HLA assignment of the entity comprises typing at least 4 HLA loci (claim 9), O’Reilly teaches the step of ascertaining the HLA assignment of the patient or of the diseased cells in the patient comprises typing at least 4 HLA (Pg. 49, claim 5).
Regarding instant claims 51-53 and newly added 63-65, wherein one or more steps of the method of claim 6 are carried out using a computer system (claim 51), wherein all the steps are carried out using a computer system (claim 52) and where the computer system comprises a central processing unit and memory for storing electronic instructions for performing one or more steps of the method (claim 53), O’Reilly teaches a computer system for selecting an allogeneic T cell line for therapeutic administration to a human patient having or suspected of having a pathogen or cancer, comprising a central processing unit, a memory coupled to the central processing unit for storing instructions for performing the selection steps (Pg.56, claims 100-101).
It would have been obvious to one having ordinary skill to combine the teachings of ‘439 with the teachings of O’Reilly and Barker to produce the method of selecting T cell lines for therapeutic administration to a human patient. One would have been motivated to do so because ‘507 teaches selection of T cells based on known activity against pathogen and O’Reilly and Barker teach the prioritization of restriction of the cell lines to alleles from the diseased entity. Barker specifically teaches that administration of EBV-CTLs restricted to two HLA alleles on the EBV+ lymphoma produced sustained complete remission after 5 infusions. Thus, Barker teaches an intentional step of selecting EBV-CTLs restricted to more than one HLA on the diseased cells of a human patient and provides evidence of effectiveness in treating EBV-PTLD. There would be an expectation of success in combining to the teachings of ‘507, Barker and O’Reilly to produce a method that requires restriction to more than one HLA allele to treat a patient because Barker teaches the efficacy of selecting T cell lines on the basis of HLA restriction to more than one HLA allele.
Response to Applicant’s Arguments
The applicants request withdrawal of the non-statutory double patenting rejections on the grounds that Application No. 17/497,439 and U.S. Patent No. 11,173,205 contain the same limitations as the disclosure of O’Reilly and the instant invention is not obvious in view Barker as expounded in the traversal of the 35 U.S.C. 103 above. As the prior art rejection is maintained for the reasons set forth in the above section, the double patenting rejections will also be maintained herein.
New Grounds of Objection
Claim Objections
Applicant is advised that should claims 6, 9-11, 13, 16, 46, 48-49, 51-53 be found allowable, newly added claims 54-65 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claims 6 and 54 differ in two ways:
In line 3, claim 54 uses the abbreviated “EBV-PTLD post HSCT or SOT” instead of spelling them out as done in claim 6 at first mention.
Claim 6 states: “wherein the method further comprises before step (a) a step of ascertaining the HLA restriction of each T cell line in the collection and a step of ascertaining the HLA assignment of the entity” and claim 54 states “wherein the HLA restriction of each T cell line in the collection and the HLA assignment of the entity have been ascertained” which both encompass the same active method step/limitation with slightly different wording.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646
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