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 .
Election/Restrictions
Applicant’s election without traverse of the species SEQ ID NO: 1 in the reply filed on April 23, 2026, is acknowledged. The elected species is free of the art. SEQ ID NOs: 4 and 7-14 are also free of the art. The search was extended and prior art was found that reads on claims 1 and 20-22 (see anticipation rejections below).
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.
Claims 1-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for 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.
The claims are to regulatory T cell inducing peptides of SEQ ID NO: 55. The peptide contains two or three adjacent copies of a motif derived from the lysine-rich motif the CTLA-4 protein cytoplasmic domain (i.e. K motif, KMLKKRS) Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4. The peptides are intended for use in the treatment and prevention of autoimmune diseases by a mechanism of inducing regulatory T cells.
BRI of claims 1, 8-17, and 20-22 include a minimum of 208 unique amino acid sequences wherein n is 2 and a minimum of 2012 unique amino acid sequences wherein n is 3.1 Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
BRI of claim 2 includes a minimum of 82x206 unique amino acid sequences wherein n is 2 and a minimum of 83x209 unique amino acid sequences wherein n is 3.2 Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
BRI of claim 3 includes a minimum of 82x34x202 unique amino acid sequences wherein n is 2 and a minimum of 83x36x203 unique amino acid sequences wherein n is 3.3 Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
BRI of claim 4 includes a minimum of 82x34x42 unique amino acid sequences wherein n is 2 and a minimum of 83x36x43 unique amino acid sequences wherein n is 3.4 Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
BRI of claim 5 includes a minimum of 12x206 unique amino acid sequences wherein n is 2 and a minimum of 13x209 unique amino acid sequences wherein n is 3. Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
BRI of claim 6 includes a minimum of 12x14x202 unique amino acid sequences wherein n is 2 and a minimum of 13x16x203 unique amino acid sequences wherein n is 3. Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
BRI of claims 7 and 18-19 include fully defined amino acid sequences. Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
Only those sequences meeting the structural and functional requirements of the genus are encompassed by the claim. Therefore, the claim encompasses all of the sequences meeting the structural requirements that are also able to induce regulatory T cells. Although with the aid of a computer it may be possible to determine the amino acid sequences of the peptides that meet the structural requirements of the claim (i.e. SEQ ID NO: 55), it is not readily apparent from the claims or the specification which of these sequences are also able to induce regulatory T cells or be used to treat or prevent autoimmune diseases.
In addition, there is a high level of unpredictability and complexity associated with structure and function for the claimed peptides. The prior art discloses numerous peptide sequences that contain SEQ ID NO: 55 (i.e. they contain adjacent copies of Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4) as claimed. See for example CRMP-5, which is a polypeptide comprising Lys-Lys-Leu-Val-Gln-Arg-Glu-Lys-Thr-Leu-Lys-Val-Arg-Gly at residues 473 to 486, as evidenced by Uniprot Q9BPU6 · DPYL5_HUMAN (Ponnusamy et al. Materials and Methods, pages 856-857). See also designed peptide ACR3, which is a peptide comprising Lys-Lys-Leu-Ala-Cys-Arg-Leu-Lys-Lys-Leu-Ala-Cys-Arg-Leu at residues 2 to 15 (Tan et al. Figure 1(E); see also CAR3, CAR4, ACR3, and ACR4 in Table 1). However, although these peptides of the prior art contain SEQ ID NO: 55, they are not taught to possess the function of regulatory T cell induction or to be useful for treating or preventing autoimmune disease. In contrast, the peptide of Tan et al. is taught to be antimicrobial and antihemolytic (Tan et al. Section 2.1). The structural genus is so broad that it is not clearly limited to peptides having the claimed structure.
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an immune checkpoint molecule that inhibits T-cell activation and regulates immune homeostasis (Kim & Choi, Fig. 1). CTLA-4, contains a single copy of a Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4 sequence in its cytoplasmic domain but does not contain SEQ ID NO: 55 which requires n is 2 or 3 (see KMLKKRS located at positions 188-194, Uniprot P16410 · CTLA4_HUMAN). Kim & Choi summarize the motifs and their interaction partners found in the cytoplasmic domain of CTLA4 (Figure 3):
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The lysine-rich motif is highlighted in pink and corresponds to one copy of the dimerized and trimerized motif of a SEQ ID NO: 55 species (CTLA-4 does not contain SEQ ID NO: 55). Kim & Choi cite prior art references (Kong et al. and Teft et al.) that show that this motif interacts with PKC-η and PP2A. In addition, the prior art of Kim et al. teach that the lysine-rich motif of CTLA-4 is critical for its function in inducing Tregs to maintain peripheral immune tolerance to control autoimmunity (abstract only). Neither Kong et al., Teft et al. nor Kim et al. teach nor suggest a peptide consisting or comprising two or three adjacent copies of KMLKKRS or suggest that an isolated copy of the motif alone could be multimerized and used for any purpose including inducing regulatory T cells and treating or preventing autoimmune diseases. In addition, the cited references do not describe the effect of changing the KMLKKRS amino acids with other amino acids, including conservative changes, on function.
The prior art does not present clear rules to distinguish peptides that can induce regulatory T cells from those that are not capable of this function. Furthermore, the prior art does not present clear rules to distinguish peptides that can treat or prevent autoimmune diseases by inducing regulatory T cells from those that are not capable of this function.
The original specification disclosed several embodiments of the invention: K2, K3, KD2, or KD3 (SEQ ID NOs: 1, 4, 11, and 12) and K2, K3, KD2, or KD3 attached to a linker, cell penetrating peptide, or fatty acid (SEQ ID NOs: 7-10 and 13-14). As discussed above the claim scope is potentially enormous depending on how many of the sequences that meet the structural requirements are also able to induce regulatory T cells; in comparison, the scope of the description which only includes species consisting of two or three adjacent copies of a single sequence KMLKKRS with or without D-amino acids and with or without attachment to a linker, CPP, or fatty acid, is extremely narrow. The actual reduction to practice does not include species characterized by sequences with different amino acids at positions X1, X2, X3, and X4. The only substitutions disclosed are single alanine substitutions which are not sufficient to probe the effect of the full range of possible amino acid side chains. In addition, the actual reduction to practice fails to include amino acids N- and/or C-terminal to SEQ ID NO: 55 other than the linker or CPP, which are separate functional moieties. Therefore, one of ordinary skill in the art would not consider K2, K3, KD2, or KD3 (SEQ ID NOs: 1, 4, 11, and 12) and K2, K3, KD2, or KD3 attached to a linker, cell penetrating peptide, or fatty acid (SEQ ID NOs: 7-10 and 13-14) to be representative of the full scope of the claimed genus.
Therefore, the instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
The specification does not disclose a partial structure of a protein that meets the structural requirements of the genus. Although from the statement “represented by… (SEQ ID NO: 55)” one of ordinary skill in the art could determine if a given amino acid sequence meets the structural requirements of the genus, it would not be possible to determine from the sequence alone if the protein is able to induce regulatory T cells. Unless all sequences having SEQ ID NO: 55 are able to induce regulatory T cells, this description alone does not constitute a partial structure for the genus.
The data in the specification do not suggest the physical basis for the regulatory T cell induction activity and therefore do not describe which substitutions, deletions or additions could be made while preserving function. Although the peptides are derived from a particular region of CTLA4 protein, the specification does not describe a mechanism of action for the peptide such as a binding partner, let alone the structural properties of the binding complex. Understanding the physical basis for inducing regulatory T cells is critical to determining which of the sequences that meet the structural requirements of the genus also meet the functional requirements of the genus.
The specification does not describe a general correlation between structure and function for the claimed genus. The role of Xaa1, Xaa2, Xaa3, and Xaa4 amino acids of SEQ ID NO: 55 are not specifically described. Although the peptides are derived from a particular region of CTLA4 protein, the specification does not describe a mechanism of action for the peptide such as a binding partner, let alone the structural properties of the binding complex. The specification is completely silent regarding a structure-function correlation specific for treatment and prevention of autoimmune diseases, including multiple sclerosis. As a result, it is impossible to predict, based on the specification, how changing any position will affect function.
Solid state peptide synthesis and the cloning, recombinant expression and purification of proteins is well-known in the art. Where the specification fails to provide description is in the structure of the peptide to make. For all of the reasons presented above, one of ordinary skill in the art would not know which of the countless peptides that meet the structural requirements of the claims would also be able to induce regulatory T cells. The specification does not make clear which peptides are in the genus and which are not because it does not describe the physical basis for the claimed activity. In other words, the specification does not describe which peptides to make.
For these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
In conclusion, only regulatory T cell inducing peptides consisting of K2, K3, KD2, or KD3 (SEQ ID NOs: 1, 4, 11, and 12) and K2, K3, KD2, or KD3 attached to a linker, cell penetrating peptide, or fatty acid (SEQ ID NOs: 7-10 and 13-14), satisfy the written description requirements of 35 U.S.C. 112.
Claims 1-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for using peptides consisting of K2, K3, KD2, or KD3 (SEQ ID NOs: 1, 4, 11, and 12) and K2, K3, KD2, or KD3 attached to a linker, cell penetrating peptide, or fatty acid (SEQ ID NOs: 7-10 and 13-14) to induce regulatory T cells in in vitro and to treat multiple sclerosis in a subject, does not reasonably provide enablement for the use of these peptides to prevent multiple sclerosis, or treat or prevent any other autoimmune disease, or for the use of any other peptide comprising SEQ ID NO: 55. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The Nature of the Invention
The claims are to regulatory T cell inducing peptides of SEQ ID NO: 55. The peptide contains two or three adjacent copies of a motif derived from the lysine-rich motif the CTLA-4 protein cytoplasmic domain (i.e. K motif, KMLKKRS) Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4. The peptides are intended for use in the treatment and prevention of autoimmune diseases by a mechanism of inducing regulatory T cells.
The breadth of the claims
BRI of claims 1, 8-17, and 20-22 include a minimum of 208 unique amino acid sequences wherein n is 2 and a minimum of 2012 unique amino acid sequences wherein n is 3.5 Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
BRI of claim 2 includes a minimum of 82x206 unique amino acid sequences wherein n is 2 and a minimum of 83x209 unique amino acid sequences wherein n is 3.6 Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
BRI of claim 3 includes a minimum of 82x34x202 unique amino acid sequences wherein n is 2 and a minimum of 83x36x203 unique amino acid sequences wherein n is 3.7 Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
BRI of claim 4 includes a minimum of 82x34x42 unique amino acid sequences wherein n is 2 and a minimum of 83x36x43 unique amino acid sequences wherein n is 3.8 Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
BRI of claim 5 includes a minimum of 12x206 unique amino acid sequences wherein n is 2 and a minimum of 13x209 unique amino acid sequences wherein n is 3. Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
BRI of claim 6 includes a minimum of 12x14x202 unique amino acid sequences wherein n is 2 and a minimum of 13x16x203 unique amino acid sequences wherein n is 3. Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
BRI of claims 7 and 18-19 include fully defined amino acid sequences. Because the transitional phrase “represented by” may be open or closed, the peptide can further contain unrecited amino acids at the N- and/or C-terminus. In addition, any of the amino acids can be in the L- or D-configuration.
Only those sequences meeting the structural and functional requirements of the genus are encompassed by the claims. Therefore, the claims encompasses all of the sequences meeting the structural requirements that are also able to induce regulatory T cells. Although with the aid of a computer it may be possible to determine the amino acid sequences of the peptides that meet the structural requirements of the claim (i.e. SEQ ID NO: 55), it is not readily apparent from the claims or the specification which of these sequences are also able to induce regulatory T cells.
Regarding claims 20-22, BRI of the intended use includes treatment and prevention of autoimmune diseases.
The State of the Prior Art
The Examiner is not aware of prior art disclosing the use of the claimed compositions to induce regulatory T cells or to treat or prevent autoimmune diseases.
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an immune checkpoint molecule that inhibits T-cell activation and regulates immune homeostasis (Kim & Choi, Fig. 1). CTLA-4, contains a single copy of a Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4 sequence in its cytoplasmic domain but does not contain SEQ ID NO: 55 which requires n is 2 or 3 (see KMLKKRS located at positions 188-194, Uniprot P16410 · CTLA4_HUMAN). Kim & Choi summarize the motifs and their interaction partners found in the cytoplasmic domain of CTLA4 (see reproduction of Figure 3 above). The lysine-rich motif is highlighted in pink and corresponds to one copy of the dimerized and trimerized motif of a SEQ ID NO: 55 species (CTLA-4 does not contain SEQ ID NO: 55). Kim & Choi cite prior art references (Kong et al. and Teft et al.) that show that this motif interacts with PKC-η and PP2A. In addition, the prior art of Kim et al. teach that the lysine-rich motif of CTLA-4 is critical for its function in inducing Tregs to maintain peripheral immune tolerance to control autoimmunity (abstract only). Neither Kong et al., Teft et al. nor Kim et al. teach nor suggest a peptide consisting or comprising two or three adjacent copies of KMLKKRS or suggest that an isolated copy of the motif alone could be multimerized and used for any purpose including inducing regulatory T cells and treating or preventing autoimmune diseases.
The Predictability or Unpredictability of the Art
There is a high level of unpredictability and complexity associated with structure and function for the claimed peptides. The prior art discloses numerous peptide sequences that contain SEQ ID NO: 55 (i.e. they contain adjacent copies of Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4) as claimed. See for example CRMP-5, which is a polypeptide comprising Lys-Lys-Leu-Val-Gln-Arg-Glu-Lys-Thr-Leu-Lys-Val-Arg-Gly at residues 473 to 486, as evidenced by Uniprot Q9BPU6 · DPYL5_HUMAN (Ponnusamy et al. Materials and Methods, pages 856-857). See also designed peptide ACR3, which is a peptide comprising Lys-Lys-Leu-Ala-Cys-Arg-Leu-Lys-Lys-Leu-Ala-Cys-Arg-Leu at residues 2 to 15 (Tan et al. Figure 1(E); see also CAR3, CAR4, ACR3, and ACR4 in Table 1). However, although these peptides of the prior art contain SEQ ID NO: 55, they are not taught to possess the function of regulatory T cell induction or to be useful for treating or preventing autoimmune disease. In contrast, the peptide of Tan et al. is taught to be antimicrobial and antihemolytic (Tan et al. Section 2.1). The structural genus is so broad that it is not clearly limited to peptides having the claimed structure.
In addition, there is a high level of unpredictability associated with treating and preventing autoimmune diseases. According to the original specification, there are over 80 recognized autoimmune diseases, including multiple sclerosis, the mechanism for which is not known. The specification reports that: “The current technology for treating autoimmune disease is an approach for alleviating symptoms or slowing down the progression thereof using anti-inflammation agents, steroids, etc. and mostly relies on empirical effects, and there is no fundamental technology that eliminates the cause of the disease. In cases of severe autoimmune disease, a method of weakening the immune function by administering an immunosuppressant is sometimes selected. But, since this treatment technology has the side effect of bringing fatal results to infectious diseases because the immune function of protecting against bacteria, etc. in healthy adults is also suppressed, it cannot be used for a long period of time.” Specification, page 3, lines 11-19.
The Level of Guidance in the Specification
The guidance provided in the specification with respect to administration and dosage is generic.
The specification does not disclose a partial structure of a protein that meets the structural requirements of the genus. Although from the statement “represented by… (SEQ ID NO: 55)” one of ordinary skill in the art could determine if a given amino acid sequence meets the structural requirements of the genus, it would not be possible to determine from the sequence alone if the protein is able to induce regulatory T cells. Unless all sequences having SEQ ID NO: 55 are able to induce regulatory T cells, this description alone does not constitute a partial structure for the genus.
The data in the specification do not suggest the physical basis for the regulatory T cell induction activity and therefore do not describe which substitutions, deletions or additions could be made while preserving function. Although the peptides are derived from a particular region of CTLA4 protein, the specification does not describe a mechanism of action for the peptide such as a binding partner, let alone the structural properties of the binding complex. Understanding the physical basis for inducing regulatory T cells is critical to determining which of the sequences that meet the structural requirements of the genus also meet the functional requirements of the genus.
The specification does not describe a general correlation between structure and function for the claimed genus. The role of Xaa1, Xaa2, Xaa3, and Xaa4 amino acids of SEQ ID NO: 55 are not specifically described. Although the peptides are derived from a particular region of CTLA4 protein, the specification does not describe a mechanism of action for the peptide such as a binding partner, let alone the structural properties of the binding complex. The specification is completely silent regarding a structure-function correlation specific for treatment and prevention of autoimmune diseases, including multiple sclerosis. As a result, it is impossible to predict, based on the specification, how changing any position will affect function.
The Presence or Absence of Working Examples
The original specification disclosed several embodiments of the invention: K2, K3, KD2, or KD3 (SEQ ID NOs: 1, 4, 11, and 12) and K2, K3, KD2, or KD3 attached to a linker, cell penetrating peptide, or fatty acid (SEQ ID NOs: 7-10 and 13-14). As discussed above the claim scope is potentially enormous depending on how many of the sequences that meet the structural requirements are also able to induce regulatory T cells; in comparison, the scope of the description which only includes species consisting of two or three adjacent copies of a single sequence KMLKKRS with or without D-amino acids and with or without attachment to a linker, CPP, or fatty acid, is extremely narrow. The actual reduction to practice does not include species characterized by sequences with different amino acids at positions X1, X2, X3, and X4. The only substitutions disclosed are single alanine substitutions which are not sufficient to probe the effect of the full range of possible amino acid side chains. In addition, the actual reduction to practice fails to include amino acids N- and/or C-terminal to SEQ ID NO: 55 other than the linker or CPP, which are separate functional moieties. Therefore, one of ordinary skill in the art would not consider K2, K3, KD2, or KD3 (SEQ ID NOs: 1, 4, 11, and 12) and K2, K3, KD2, or KD3 attached to a linker, cell penetrating peptide, or fatty acid (SEQ ID NOs: 7-10 and 13-14) to be representative of the full scope of the claimed genus.
The specification reduces to practice an animal model for a single autoimmune disease, multiple sclerosis. One of ordinary skill in the art would not consider this animal model to be predictive for prevention of multiple sclerosis nor would one of ordinary skill in the art consider this animal model to be predictive for 80 different autoimmune disorders.
The Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if one of the claimed peptides would be effective at inducing regulatory T cells. The skilled artisan would be burdened with testing a broad range of peptides in in vitro assays. The active peptides would then have to be subjected to animal models specific for the autoimmune disease to be treated. The experimentation required represents years of inventive effort. When the above factors are weighed, it is the examiner's position that one skilled in the art could not practice the invention without undue experimentation.
Therefore, in view of the Wands factors, the claims appear to require undue experimentation to use the full scope of the claimed invention.
Claim Rejections - 35 USC § 112(b)
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 1-22 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.
In claim 1, the indefinite language is: “represented by”.
BRI of this limitation includes multiple, plausible constructions: 1) open construction, which permits additional, unclaimed elements in the regulatory T cell-inducing peptide and 2) closed construction, which excludes additional, unclaimed elements in the regulatory T cell-inducing peptide. The specification fails to provide a limiting definition of the transitional phrase “represented by”. Several dependent claims appear to support the open construction because they recite linkers, cell penetrating peptides, and lipids. However, even these claims fail to clearly define the phrase “represented by” because the regulatory T cell-inducing peptide itself could be limited to peptides consisting of SEQ ID NO: 55 and then additionally be attached to separate elements that are not considered regulatory T cell inducing peptides such as linkers, cell penetrating peptides, and lipids (i.e. a conjugate consisting of a regulatory T cell inducing peptide and a separate linker, cell penetrating peptide, and/or lipid). It is not clear if the claimed peptide having regulatory T cell inducing function can include amino acid residues N- and/or C-terminal to [Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4]n that contribute to this function or if these N- and/or C-terminal residues are excluded from the claim.
The language is indefinite because it is not clear which construction is covered (e.g., because there is more than one reasonable interpretation of what construction is included in the claim). See MPEP § 2173.04.
Dependent claims 2-22 fail to remedy this issue and are likewise rejected.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 18 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 18 recites SEQ ID NO: 2. SEQ ID NO: 2 is not part of the genus of SEQ ID NO: 55 in claim 1 because it does not contain n=2 or 3 adjacent copies of [Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4]. In SEQ ID NO: 2 the linker sequence GGGS is located between the two copies of the sequence corresponding to [Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4], which is not permitted by the formula in claim 1.
Claim 18 recites SEQ ID NO: 3. SEQ ID NO: 3 is not part of the genus of SEQ ID NO: 55 in claim 1 because it does not contain n=2 or 3 adjacent copies of [Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4]. In SEQ ID NO: 3 the linker sequence GG is located between the two copies of the sequence corresponding to [Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4], which is not permitted by the formula in claim 1.
Claim 18 recites SEQ ID NO: 5. SEQ ID NO: 5 is not part of the genus of SEQ ID NO: 55 in claim 1 because it does not contain n=2 or 3 adjacent copies of [Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4]. In SEQ ID NO: 5 the linker sequence GGGS is located between each copy of the sequence corresponding to [Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4], which is not permitted by the formula in claim 1.
Claim 18 recites SEQ ID NO: 6. SEQ ID NO: 6 is not part of the genus of SEQ ID NO: 55 in claim 1 because it does not contain n=2 or 3 adjacent copies of [Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4]. In SEQ ID NO: 6 the linker sequence GG is located between each copy of the sequence corresponding to [Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4], which is not permitted by the formula in claim 1.
Claim 18 recites SEQ ID NO: 51. SEQ ID NO: 51 is not part of the genus of SEQ ID NO: 55 in claim 1 because it does not contain n=2 or 3 adjacent copies of [Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4]. In SEQ ID NO: 51 the Leu in the third position of [Lys-Xaa1-Leu-Xaa2-Xaa3-Arg-Xaa4] is replaced with Ala, which is not permitted by the formula in claim 1.
Therefore, claim 18 does not include all of the limitations of the claim from which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 20-22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
Regarding claim 1, BRI of the claim includes a peptide with the amino acid sequence Lys-Lys-Leu-Val-Gln-Arg-Glu-Lys-Thr-Leu-Lys-Val-Arg-Gly, which corresponds to SEQ ID NO: 55 wherein n is 2, Xaa1 is Lys or Thr, Xaa2 is Val or Lys, Xaa3 is Gln or Val, and Xaa4 is Glu or Gly.
Step 1: Claim 1 is to a composition of matter.
Step 2A, Prong 1: Claim 1 is directed to a product of nature, the peptide Lys-Lys-Leu-Val-Gln-Arg-Glu-Lys-Thr-Leu-Lys-Val-Arg-Gly. The closest counterpart to the nature-based product is dihydropyrimidinase-related protein 5 (DRP-5) from homo sapiens.9 The claimed peptide corresponds to residues 473 to 486 of DRP-5, as evidenced by Uniprot entry Q9BPU6 · DPYL5_HUMAN. The claimed peptide has a different structural characteristic than the natural peptide, i.e., the natural peptide has covalent bonds on its ends that connect it to the rest of the protein whereas the claimed peptide lacks these bonds. However, the claimed peptide is otherwise structurally identical to the natural peptide, e.g., they had the same peptide backbone and amino acid sequence as DRP-5 in nature. This difference is not a marked difference in view of MPEP § 2106.04(c)(II)(C)(2) and the Supreme Court decision in Myriad. See, e.g., Myriad, 569 U.S. at 585, 106 USPQ2d at 1977. In addition, the function of the claimed peptide, regulatory T cell-inducing, is innate to the peptide itself, and was not created or altered by the inventor. See Ambry Genetics, 774 F.3d at 760-61, 113 USPQ2d at 1244. In sum, the claimed peptide is different, but not markedly different, from its naturally occurring counterpart (DRP-5), and thus is a natural phenomenon exception.
Step 2A, Prong 2: The claim only recites the peptide, which is a natural phenomenon exception. Because there are no additional claim elements besides the judicial exception, the judicial exception is not integrated into a practical application (MPEP § 2106.04(d)(III)).
Step 2B: The claim only recites the peptide, which is a natural phenomenon exception. Because there are no additional claim elements besides the judicial exception, the claim does not amount to significantly more than the judicial exception (MPEP § 2106.05).
Therefore, claim 1 is patent ineligible.
Regarding claims 20-22, The claim only recites the peptide, which is a natural phenomenon exception. Because the limitation “pharmaceutical composition for preventing or treating autoimmune disease” does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration (MPEP § 2106.04(d)(2)) nor does it amount to significantly more than the judicial exception (MPEP § 2106.05).
Therefore, claims 20-22 are patent ineligible.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ponnusamy et al. (Insights into the oligomerization of CRMPs: crystal structure of human collapsin response mediator protein 5. J. Neurochem. (2013) 125, 855-868).
BRI of claim 1 includes a polypeptide comprising the amino acid sequence Lys-Lys-Leu-Val-Gln-Arg-Glu-Lys-Thr-Leu-Lys-Val-Arg-Gly, which corresponds to SEQ ID NO: 55 wherein n is 2, Xaa1 is Lys or Thr, Xaa2 is Val or Lys, Xaa3 is Gln or Val, and Xaa4 is Glu or Gly.
Ponnusamy et al. teach CRMP-5, which is a polypeptide comprising Lys-Lys-Leu-Val-Gln-Arg-Glu-Lys-Thr-Leu-Lys-Val-Arg-Gly at residues 473 to 486, as evidenced by Uniprot Q9BPU6 · DPYL5_HUMAN (see Materials and Methods, pages 856-857).
Ponnusamy et al. teaches a peptide that meets the structural limitations of claim 1 but is silent as to the function of regulatory T cell induction. Burden is shifted to Applicant to determine if the peptide disclosed Ponnusamy et al. possesses the claimed function.
MPEP § 2112.01(II) states: "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.
In the instant case, the prior art teaches a peptide that meets the structural limitations of claim 1 but is silent as to the function of regulatory T cell induction. Because the prior art teaches a composition that meets all of the structural and physical limitations of the claim, the claimed property of regulatory T cell induction is inherent to the prior art composition.
As a practical matter, the Patent Office is not equipped to test the peptide of Ponnusamy et al. for the claimed function. The burden is shifted to Applicant to establish whether the prior art products inherently possess the characteristics of the claimed product. MPEP § 2112(V).
Claims 1 and 20-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tan et al. (Design of Heptad Repeat Amphiphiles Based on Database Filtering and Structure−Function Relationships to Combat Drug-Resistant Fungi and Biofilms. ACS Appl. Mater. Interfaces 2020, 12, 2129-2144).
BRI of claim 1 includes a polypeptide comprising the amino acid sequence Lys-Lys-Leu-Ala-Cys-Arg-Leu-Lys-Lys-Leu-Ala-Cys-Arg-Leu, which corresponds to SEQ ID NO: 55 wherein n is 2, Xaa1 is Lys, Xaa2 is Ala, Xaa3 is Cys, and Xaa4 is Leu.
Tan et al. teach designed peptide ACR3, which is a peptide comprising Lys-Lys-Leu-Ala-Cys-Arg-Leu-Lys-Lys-Leu-Ala-Cys-Arg-Leu at residues 2 to 15 (see Figure 1(E); see also CAR3, CAR4, ACR3, and ACR4 in Table 1).
Tan et al. teaches a peptide that meets the structural limitations of claim 1 but is silent as to the function of regulatory T cell induction. Burden is shifted to Applicant to determine if the peptide disclosed Tan et al. possesses the claimed function.
MPEP § 2112.01(II) states: "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.
In the instant case, the prior art teaches a peptide that meets the structural limitations of claim 1 but is silent as to the function of regulatory T cell induction. Because the prior art teaches a composition that meets all of the structural and physical limitations of the claim, the claimed property of regulatory T cell induction is inherent to the prior art composition.
As a practical matter, the Patent Office is not equipped to test the peptide of Tan et al. for the claimed function. The burden is shifted to Applicant to establish whether the prior art products inherently possess the characteristics of the claimed product. MPEP § 2112(V).
Regarding claims 20-22, Tan et al. teach that the peptides have antimicrobial activity (Section 2.1). Therefore, the peptides taught by Tan et al. are suitable for use as pharmaceutical compositions. Regarding the diseases and conditions recited in these claims, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Allowable Subject Matter
The following claims drafted by the examiner and considered to distinguish patentably over the art of record in this application, are presented to applicant for consideration:
Replace claim 1 with the following
1. A regulatory T cell-inducing peptide selected from the group consisting of
(KMLKKRS)2 (SEQ ID NO: 1),
(KMLKKRS)3 (SEQ ID NO: 4),
(DLys-DMet-LKK-DArg-DSer)2 (SEQ ID NO: 11), and
(DLys-DMet-LKK-DArg-DSer)3 (SEQ ID NO: 12),
wherein the regulatory T cell-inducing peptide is optionally attached to a fatty acid or cell penetrating peptide (CPP) at the N- or C-terminus.
Cancel claims 2-11.
12. The regulatory T cell-inducing peptide according to claim 1, wherein the regulatory T cell-inducing peptide is attached to a fatty acid at the N- or C-terminus
13. The regulatory T cell-inducing peptide according to claim 12, wherein the fatty acid is attachedus[[al]] of the regulatory T cell-inducing peptide via an amide bond.
Claims 14-15 are as previously presented.
16. The regulatory T cell-inducing peptide according to claim 1, wherein the regulatory T cell-inducing peptide is attached to a cell penetrating peptide (CPP) at the N- or C-terminus, optionally via a linker
Claim 17 is as previously presented.
18. The regulatory T cell-inducing peptide according to claim 1, wherein the regulatory T cell-inducing peptide is any one selected from the group consisting of SEQ ID NOs: 1, 4, 11, and 12
19. The regulatory T cell-inducing peptide according to claim 16, wherein the regulatory T cell-inducing peptide s:[[S]] 7-10, SEQ ID NO: 13 and SEQ ID NO 14.
20. A pharmaceutical composition for multiple sclerosis
Cancel claim 21.
22. The pharmaceutical composition for multiple sclerosish17 and activates Treg.
The following is a statement of reasons for the indication of allowable subject matter: the closest prior art is Kim et al. (The cytoplasmic domain of CTLA-4 control autoimmunity via inducing regulatory T cells, The Journal of Immunology, Volume 202, Issue 1_Supplement, May 2019, Page 193.4, Abstract only). Kim et al. teach that the lysine-rich motif of CTLA-4 is critical for its function in inducing Tregs to maintain peripheral immune tolerance to control autoimmunity. Kim et al. do not teach nor suggest a peptide consisting of or comprising two or three adjacent copies of KMLKKRS (i.e. KMLKKRSKMLKKRS or KMLKKRSKMLKKRSKMLKKRS). Therefore, the claims suggested above are novel and unobvious over Kim et al.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
1 There are 20 options for each of Xaa1, Xaa2, Xaa3, and Xaa4 and each occurrence of Xaa1, Xaa2, Xaa3, and Xaa4 is independently defined. Therefore, when n is 2, SEQ ID NO: 55 includes 20x20x20x20x20x20x20x20 sequences, and when n is 3, SEQ ID NO: 55 includes 20x20x20x20x20x20x20x20 x20x20x20x20 sequences.
2 There are 8 options for Xaa1 and 20 options for each of Xaa2, Xaa3, and Xaa4 and each occurrence of Xaa1, Xaa2, Xaa3, and Xaa4 is independently defined. Therefore, when n is 2, SEQ ID NO: 55 includes 8x20x20x20x8x20x20x20 sequences, and when n is 3, SEQ ID NO: 55 includes8x20x20x20x8x20x20x20x8x20x20x20 sequences.
3 There are 8 options for Xaa1, 3 options for each of Xaa2 and Xaa3, and 20 options for Xaa4 and each occurrence of Xaa1, Xaa2, Xaa3, and Xaa4 is independently defined. Therefore, when n is 2, SEQ ID NO: 55 includes 8x3x3x20x8x3x3x20 sequences, and when n is 3, SEQ ID NO: 55 includes8x3x3x20x8x3x3x20x8x3x3x20 sequences.
4 There are 8 options for Xaa1, 3 options for each of Xaa2 and Xaa3, and 4 options for Xaa4 and each occurrence of Xaa1, Xaa2, Xaa3, and Xaa4 is independently defined. Therefore, when n is 2, SEQ ID NO: 55 includes 8x3x3x4x8x3x3x4 sequences, and when n is 3, SEQ ID NO: 55 includes8x3x3x4x8x3x3x4x8x3x3x4 sequences.
5 There are 20 options for each of Xaa1, Xaa2, Xaa3, and Xaa4 and each occurrence of Xaa1, Xaa2, Xaa3, and Xaa4 is independently defined. Therefore, when n is 2, SEQ ID NO: 55 includes 20x20x20x20x20x20x20x20 sequences, and when n is 3, SEQ ID NO: 55 includes 20x20x20x20x20x20x20x20 x20x20x20x20 sequences.
6 There are 8 options for Xaa1 and 20 options for each of Xaa2, Xaa3, and Xaa4 and each occurrence of Xaa1, Xaa2, Xaa3, and Xaa4 is independently defined. Therefore, when n is 2, SEQ ID NO: 55 includes 8x20x20x20x8x20x20x20 sequences, and when n is 3, SEQ ID NO: 55 includes8x20x20x20x8x20x20x20x8x20x20x20 sequences.
7 There are 8 options for Xaa1, 3 options for each of Xaa2 and Xaa3, and 20 options for Xaa4 and each occurrence of Xaa1, Xaa2, Xaa3, and Xaa4 is independently defined. Therefore, when n is 2, SEQ ID NO: 55 includes 8x3x3x20x8x3x3x20 sequences, and when n is 3, SEQ ID NO: 55 includes8x3x3x20x8x3x3x20x8x3x3x20 sequences.
8 There are 8 options for Xaa1, 3 options for each of Xaa2 and Xaa3, and 4 options for Xaa4 and each occurrence of Xaa1, Xaa2, Xaa3, and Xaa4 is independently defined. Therefore, when n is 2, SEQ ID NO: 55 includes 8x3x3x4x8x3x3x4 sequences, and when n is 3, SEQ ID NO: 55 includes8x3x3x4x8x3x3x4x8x3x3x4 sequences.
9 Also known as CRMP3-associated molecule (CRAM), Collapsin response mediator protein 5 (CRMP-5), and
UNC33-like phosphoprotein 6 (ULIP-6)
Prosecution Insights