DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election of group I, claims 1, 3, 7-12, 20-21, and 24-25, in the reply filed on 12/30/25, is acknowledged. Upon reconsideration, the restriction requirement between group 1 and 2, as set forth in the restriction requirement mailed 10/30/25, is withdrawn. Claims 58-59 are withdrawn as being directed to a non-elected group (group 3). Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1, 3, 7-12, 20-21, 24-25, 33-34, 37-38, 46, and 50 are being acted upon.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 7-12, 20-21, 24-25, 33-34, 37-38, 46, and 50 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The scope of the claimed methods is unclear and indefinite since the metes and bounds of “recipient antigen-specific T cells” is unclear. For example, “recipient antigen” would ordinarily mean an antigen of recipient type, i.e. that originates from the recipient of a transplant. However, the specification on page 22 discloses that “recipient antigen” refers to an antigen derived from the recipient of a tissue transplant, and that it can be derived from the allogenic transplant that is produced by the recipient. In other words, the “recipient antigen” of the claims would appear to actually encompass allogeneic donor antigen from the transplant.
The same is true for “recipient antigen presenting cells”. The specification discloses recipient antigen presenting cells refers to immune cells taken from the recipient of an allogenic transplant, and that in embodiments the recipient antigen presenting cells are derived from the transplanted tissue from the recipient of an allogenic transplant. In other words, the “recipient antigen presenting cells” appear to also encompass donor type APCs that originate form the allogeneic transplant. Given that a recipient antigen in the claims could be donor antigen and a recipient antigen presenting cells could be donor antigen presenting cells, the scope of the claimed method is rendered unclear and indefinite. For example, would the claims require administration or formation of regulatory T cells that can actually recognize recipient antigen that originates in the recipient or not. Could the regulatory T cells actually be donor specific, if the donor antigen is one that resides on the transplant in the recipient?
Furthermore, in claim 7, if the “recipient antigen presenting cells” encompass those of donor type originating from the donor tissue transplant, how are “recipient antigen specific regulatory T cells formed”? In that situation, the Tregs and APCs are both from the same subject and it is unclear what the “recipient antigen” would be? A similar issue exists for claim 20. Additionally, if the “recipient antigen” can be a donor antigen, how are donor Tregs responding to it to form ‘recipient antigen specific T regs”. The same issue exists in claims 33 and 46.
It is also noted that claims 33 and 46 recite that the regulatory T cells are “from” a donor of a tissue transplant and that the recipient antigen presenting cells are “from” a subject who has received said tissue transplant. It is not clear what this is meant to encompass. Other dependent claims recite the limitation of “taken from” a particular subject, however, it appears that claims 33 and 46 are intended to be broader than this, for example encompassing cells “derived from” said subjects. The instant specification on page 25 discloses that “derived from” indicates from the stated source at some point in time. Therefore, it is not clear if the claim requires that the antigen presenting cells have been taken from a subject who has received a transplant, i.e. taken after transplantation. Or would the claims encompass regulatory T cells that are derived from the recited subjects at any time, wherein they could be derived from the subject who has received a transplant prior to receiving said transplant. For the purposes of applying prior art, the recitation of a recipient APC from a subject who has received said tissue transplant is being interpreted as encompassing a recipient APC derived from said subject at some point in time, i.e. the APC could be derived prior to transplant from the subject who ultimately received the transplant. If the other interpretation is desired, it is suggested to amend claims 33 and 46 to recite that the cells are “taken from” the subject.
Claim 10 is indefinite in the recitation of a “recipient” antigen presenting cell that is “taken from said subject’s tissue transplant”. How can the APC be both recipient and taken from a (donor) tissue transplant? For example, if the transplant is a liver tissue transplant, antigen presenting cells taken from said liver tissue would be donor antigen presenting cells. Do the claims encompass taking antigen presenting cells from the blood of a recipient subject with a transplant, if it contains antigen presenting cells derived from the transplant? Do the claims require taking the antigen presenting cells directly from the tissue used for transplant? The scope of the claim is unclear and indefinite.
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.
Claims 1, 3, 7-12, 20-21, 24-25, 33-34, 37-38, 46, and 50 are rejected under 35 U.S.C. 112, 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 specification disclosure is insufficient to enable one skilled in the art to practice the invention as claimed without an undue amount of experimentation. Undue experimentation must be considered in light of factors including: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill in the art, the level of predictability of the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention, see In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) states, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” “The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling” (MPEP 2164.03). The MPEP further states that physiological activity can be considered inherently unpredictable. With these teachings in mind, an enabling disclosure, commensurate in scope with the breadth of the claimed invention, is required.
The present claims are directed to methods of treating GVHD in a subject by administering recipient antigen specific regulatory T cells or methods of forming recipient antigen specific regulatory T cells by expanded regulatory T cells from a tissue transplant donor with a plurality of recipient antigens presenting cells. The state of the art is such that GVHD is initiated after allogeneic bone marrow transplantation, wherein donor T cells originating from the donor bone marrow recognize and attack the host (recipient). Regulatory T cells from the transplant donor can suppress GVHD when they are activated in response to recipient (host) APC cells (see the 20030147865, cited below). In this situation, the donor regulatory T cells are activated to expand in response to allogeneic recipient antigens, and the Tregs upon administration to the recipient, will suppress the aberrant immune response against the same recipient antigens that are the cause of GVHD.
However, the present claims are much broader than this. For example, the instant specification on page 22 discloses that “recipient antigen” refers to an antigen derived from the recipient of a tissue transplant, and that it can be derived from the allogenic transplant that is produced by the recipient. In other words, the “recipient antigen” of the claims would also encompass allogeneic donor antigen from the transplant. The same is true for “recipient antigen presenting cells”. The specification discloses recipient antigen presenting cells refers to immune cells taken from the recipient of an allogenic transplant, and that in embodiments the recipient antigen presenting cells are derived from the transplanted tissue from the recipient of an allogenic transplant. In other words, the “recipient antigen presenting cells” would also encompass donor type APCs that originate from the allogeneic transplant.
For example, in the claimed methods, if the “recipient antigen presenting cells” are of donor type originating from the donor tissue transplant, it would be highly unpredictable as to how “recipient antigen specific regulatory T cells” could even be formed. If there is no foreign/alloantigen, what would induce said T cells to form into antigen specific T cells? Additionally, if the “recipient antigen” can be a donor antigen, obtaining donor Tregs that would form ‘recipient antigen specific T regs” would also be highly unpredictable.
Regarding claims 33 and 46, they appear to encompass taking the antigen presenting cells directly from the subject who has received the tissue transplant. The preferred embodiment disclosed by the instant specification is a bone marrow transplant. A patient who has received a bone marrow transplant would comprise donor type APCs, and using said donor type APCs, to expand “recipient antigen” specific T cells would be highly unpredictable. A similar issue exists for claims 10-11, 24, and 37. These claims recite that the recipient antigen presenting cells are taken from said subject when the subject has GVHD. In other words, the recipient antigen presenting cells are taken after bone marrow transplant, when the recipients immune cells (including APCs) in the blood have been replaced by those originating from the donor bone marrow used for transplant. See Chakraverty, 2007, after bone marrow transplantation and GVHD onset, the APC environment undergoes dramatic distortion. The types phenotype and function of APCs after bone marrow transplantation is highly variable and dependent on the time following transplantation, the mode of conditioning, the site, and the stage of GVHD (See page 10 and 13, in particular). Furthermore, the state of the art is that it is host (recipient) APC that expand alloantigen donor T regs (see Chakraverty page 14, in particular). See also Young, 2012, which teaches that donor B cells in particular augment CD4 T cell expansion an a way that is pathogenic and exacerbates GVHD. Thus, producing recipient Treg cells and treating GVHD with said Treg cells, wherein the Tregs are produced using recipient APCs that are taken from the subject that has graft versus host disease, would be highly unpredictable. Regarding claim 10, it appears that this requires using donor type APCs from the tissue transplant, but again how this could be used to induce recipient antigen specific T cells that could treat GVHD is unclear, and would also be highly unpredictable.
Based on the unpredictably of the art and the breadth of the claim limitations, the instant specification must provide a sufficient and enabling disclosure commensurate in scope with the instant claims. The specification does not provide any examples of treating GVHD or any guidance on providing recipient antigen or recipient antigen presenting cells, including from the subject after GVHD onset, or originating from the donor as broadly encompassed by the instant claims. In Figure 1 and the examples, it appears that the experiments are performed PBMC from the patient are frozen (i.e. obtained prior to transplant) and mixed with Tregs from a donor to induce Tregs. This is similar to the prior art process taught below, which although is within the scope of some of the claims, is not commensurate in scope with the breadth of the present claims. No other guidance is provided Thus, based on the unpredictability of the art, the breadth of the claims, and the lack of guidance provided by the instant specification, it would require undue experimentation to practice the full scope of the claimed methods.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by 20030147865.
The ‘865 publication teaches a method of treating GVHD after bone marrow tissue transplantation from a donor in a recipient subject in need thereof, comprising administering Tregs. The ‘865 publication teaches that the Tregs are donor Tregs that are cultured and stimulated in vitro with antigen presenting cells from the recipient to expand the Treg cells such that they are specific to recipient type alloantigen (i.e. recipient antigen specific regulatory T cells, see pages 1-3, paragraphs 15, 28-29, in particular). The ‘865 publication teaches that the donor Treg cells are obtained from the blood of the donor (see page 6 and paragraph 27, in particular).
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 1, 3, 7-9, 12, 20-21, 25, 33-34, 38, 46, 50 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 20030147865, in view of US 20160046715 and Davies, 2009.
The teachings of the ‘865 publication are described above. The ‘865 publication teaches that the recipient antigen presenting cells are isolated prior to transplantation, i.e. prior to administration of a GVHD treatment (see paragraph 28, in particular). The ‘865 publication teaches that the APCs are from peripheral blood (See paragraph 16, in particular).
The reference differs from the claimed invention in that it does not explicitly teach contacting said regulatory T cells and recipient antigen presenting cells with a CD28 inhibitor compound or contacting the APCs with a recipient antigen.
The ‘715 publication teaches that co-culture of donor and recipient allogeneic PBMCS in the presence of anti-CD86 and anti-CD80 antibodies (i.e.CD28 inhibitor compound) expands Tregs. The ‘715 publication teaches that the process can be repeated, i.e. recovering the Treg cells and restimulating with allogeneic PBMCS in the presence of anti-CD86 and anti-CD80 to expand Tregs (see Table 1, Tregs are expanded). The ‘715 publication also teaches that the cultures are done in the presence of patient plasma, i.e. contacting with “recipient antigen” to provide activated APCs (see, for example paragraph 97).
Likewise, Davies teaches a method of treating GVHD comprising co-culturing donor T cells, with recipient PBMCs (i.e. recipient APCs) in the presence or anti-B7.1/B7.2 antibodies (i.e. CD28 inhibitor) to induce alloanergization. Davies teaches that the alloanergization process in the presence of the costimulatory molecule blockage expands Treg cells in vitro (See page 6 and supplemental figures , in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to include anti-B7 antibodies, as taught by the ‘715 publication and Davies, in the regulatory T cell cultures with recipient antigen presenting cells of the ‘865 publication. This would be within the scope of steps (a) and (b) as recited in the present claims. For example, in the cultures, the regulatory T cells expand to form a plurality of Tregs, and said plurality of Tregs is in contact with said APCs and CD28 inhibitory compound. Alternatively, step (a) of the present claims could be met by the first culture and step (b) could be met with the restimulation culture of the prior art process . The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because the ‘865 publication teaches that the Tregs expand in response to the recipient, allogeneic antigens which is important for treating GHVD (see, for example, paragraph 17 and 50), and the ‘715 publication and Davies teach that including anti-B7 antibodies acts to expand alloantigen specific Tregs. It would be obvious to repeat the expansion step again with alloantigen (i.e. recipient APCs) and said B7 antibodies to further expand Tregs as taught by the cited references.
Said APC taught above have been derived from the recipient who has received a transplant at some point in time (i.e. before the transplant), and therefor are within the scope of APCs “from a recipient subject who has received a tissue transplant”.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644