Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/18/26 has been entered.
Applicant’s amendment and response filed 2/18/26 is acknowledged and has been entered.
2. Applicant is reminded of Applicant's election without traverse of Group I and species of HLA-A*02:01 monomer, SEQ ID NO: 6 peptide ligand, SEQ ID NO: 2 first linker polypeptide comprising an enzyme-cleavable portion, SEQ ID NO: 3 as the second linker polypeptide, SEQ ID NO: 9 as the b2m polypeptide, and SEQ ID NO: 11 (HLA-A2*:01) for the heavy chain for the mature MHC-I heavy chain polypeptide bearing the BirA recognition motif in Applicant’s amendment filed 11/4/21.
Claims 1, 3-5, 8, 9, 11-15, 29, 30 and 32 are presently being examined.
3. 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.
4. Claims 1, 3-5, 8, 9, 11-15, 29, 30 and 32 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. (This is a written description rejection.)
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). "Compliance with the written description requirement is essentially a fact-based inquiry that will ‘necessarily vary depending on the nature of the invention claimed.’" Enzo Biochem, 323 F.3d at 963, 63 USPQ2d at 1612. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP 2163 I.A.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." See MPEP 2163 II.3.
Applicant has broadly claimed:
1) a single chain fusion protein (or single chain trimer, SCT) comprising, in order from N-terminus to C-terminus, a peptide ligand, a first linker polypeptide comprising an enzyme-cleavable portion, a b2m polypeptide, a second linker polypeptide, and a mature MHC-I heavy chain polypeptide, and wherein the peptide ligand comprises an amino acid sequence set forth in SEQ ID NO: 4, 5, 6, 7 or 8 (as is recited in instant base claim 1), and including the limitations of its dependent claims; and
2) a single chain fusion protein (or single chain trimer, SCT) comprising, in order from N-terminus to C-terminus, a peptide ligand, a first linker polypeptide comprising an enzyme-cleavable portion, a b2m polypeptide, a second linker polypeptide, and a mature MHC-I heavy chain polypeptide, and wherein the peptide ligand comprises an amino acid sequence set forth in SEQ ID NO: 4, 5, 6, 7 or 8 and wherein the MHC-I heavy chain polypeptide comprises an amino acid sequence set forth in SEQ ID NO: 10, SEQ ID NO: 11 or SEQ ID NO: 12 (as is recited instant claim 32); and
3) a method of peptide exchange comprising the recited steps and using the fusion protein ingredient of claim 1 or the complexed multimer ingredient of claim 13, and including the other recited limitations (claims 29 and 30).
4) a single chain fusion protein (or single chain trimer, SCT) comprising, in order from N-terminus to C-terminus, a peptide ligand, a first linker polypeptide comprising an enzyme-cleavable portion, a b2m polypeptide, a second linker polypeptide, and a mature MHC-I heavy chain polypeptide, and wherein the peptide ligand comprises an amino acid sequence set forth in SEQ ID NO: 4, 5, 6, 7 or 8 and wherein the fusion protein comprises an amino acid sequence set forth in SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, or SEQ ID NO: 19.
As such, the recitation of the open transitional phrase “comprises” preceding “an amino acid sequence set forth in” one of SEQ ID NOs: 4-8 encompasses peptide sequences that “comprise” the recited sequences set forth in one of SEQ ID NOs: 4-8 or that “comprise” a subsequence of one of the sequences set forth in one of SEQ ID NOs: 4-8 (the latter due to the recitation of “an” amino acid sequence rather than ‘the’ amino acid sequence). Thus, the peptide ligands are described by partial structure. Even wherein the claims encompass a peptide that consists of the amino acid sequence of one of SEQ ID NO: 4-8, the claims do not recite the identity of the mature MHC-I heavy chain that is comprised in the single chain fusion protein that is the binding partner of the peptide, i.e., the peptide must possess the functional property of binding to a particular MHC class I molecule and visa versa. Nor does the specification disclose longer peptides or subsequences of the recited peptides (plus or minus extra N- and/or -C-flanking amino acid sequences appended thereon) that possess the functional property of binding to a MHC-I heavy chain. In the case of instant claim 12, although the claim recites SEQ ID NO: 15-19, it also recites “wherein the fusion protein comprises an amino acid sequence set forth in SEQ ID NO: 15…”, i.e., it recites a partial sequence of the fusion protein by the recitation of “an” instead of ‘the’.
The specification discloses that the peptide that consists of the sequence corresponding to SEQ ID NO: 4 binds to one species of human MHC class I molecule HLA-A*11:01, that the peptide that consists of the sequence corresponding to SEQ ID NO: 5 binds to one species of human MHC class I molecule HLA-A*11:01, that the peptide that consists of the sequence corresponding to SEQ ID NO: 6 or SEQ ID NO: 7 binds to one species of human MHC class I molecule HLA-A2, and that the peptide that consists of the sequence corresponding to SEQ ID NO: 8 binds to one species of human MHC class I molecule HLA-A*01:01 (see below).
One of skill in the art was aware that the genus of MHC class I molecules is a large and structurally diverse genus, wherein the main diversity occurs in the peptide binding region of the MHC-I and wherein the ends of the MHC-I binding groove are closed, restricting the length of peptides that can bind therein. One of skill in the art was equally aware that there is not a structure/function relationship for the primary amino acid sequence of a peptide and the functional property of binding to a particular MHC molecule. Although prediction algorithms exist, each predicted peptide must be tested to ascertain if the peptide actually binds to a particular MHC class I molecule. These points are discussed in more detail below.
The instant claims (except for claim 32 that recites the sequence identifier for a particular HLA class I molecule) recite a single chain fusion protein/multimer thereof (or a method that uses said protein or multimer) that comprises any of the over 25,000 different highly polymorphic MHC class I heavy chains that exist in humans alone (see evidentiary reference HLA Nomenclature 2023, 2 pages, of record). (Instant claim 32, as enunciated above, is included in this rejection due to the issue of a longer peptide or a subsequence of a peptide (plus or minus additional flanking amino acid residues), even with recitation of a particular species of HLA class I molecule.)
As stated above, neither the specification nor the art disclose which MHC class I chains in the entire genus of MHC class I heavy chains are the binding partner for these said peptide ligands except for HLA-A*11:01 (for SEQ ID NO: 4 and 5, paragraph spanning pages 7-8 and page 8 at lines 7-9, respectively), HLA-A2 (for SEQ ID NO: 6 and 7, page 8 at lines 26-28 and page 9 at lines 21-23, respectively), or HLA-A*01:01 (for SEQ ID NO: 8, page 10 at lines 1-3). Note that instant dependent claim 9 also recites class I heavy chains from the subgenus’ of all HLA-A, -B, and -C, as well as a subset of rat and murine class I MHC heavy chains.
The peptide ligand comprised in the single chain fusion protein must possess the functional property of binding or associating with the peptide binding site/groove of a MHC-I heavy chain in complex with b2m (see below for disclosure in the specification for a “stabilizing peptide”, which must possess additional functional properties).
The specification does not disclose a representative number of species of such single chain fusion protein, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function, for other than the respective HLA molecules enunciated above for SEQ ID NO: 4-8. The specification does not disclose which peptides that are longer than SEQ ID NO: 4-8 possess the functional property of binding to any MHC-I molecule, nor any species of subsequences of SEQ ID NO: 4-8 alone or with flanking amino acid sequences that possess the functional property of binding to any MHC-I molecule.
Although the sequences of the MHC-I heavy chains are known for humans and for some of the non-human animals that have them, the identity of the peptide ligands for each individual MHC-I heavy chain are not known until a method to discover them is employed (and visa versa) as there is no structure/function relationship between the primary sequence of a MHC-I heavy chain (in complex with b2m) and the primary sequence of a peptide that will bind. These said considerations are evidenced for example, as follows:
One of skill in the art was aware that HLA class I molecules are extremely polymorphic, and the polymorphisms primarily reside in the area of the peptide binding groove formed by the alpha 1 and alpha 2 domains of the HLA class I heavy chain (as is evidenced by Liu et al (MHC Complex: Interaction with Peptides. IN: eLS. John Wiley & Sons, Ltd: Chichester, DOI: 10.1002/9780470015902.a0000922.pub2, 2011, pages 1-12, see entire reference, e.g., Overall Structure and Peptide Binding Groove sections, of record). Thus, the genus of HLA molecules is very large and structurally diverse, particularly within the peptide binding groove of the HLA molecules.
Evidentiary reference Wieczorek et al (Front. Immunol. 2017, volume 8, article 292: 1-16, of record) teaches that the groove in between the a1 and a 2 domains helices of MHC class I molecules accommodates peptides based on the formation of a set of conserved hydrogen bonds between the side chains of the MHC molecule and the backbone of the peptide and the occupation of defined pockets by peptide side chain anchor residues. Wieczorek et al teach that the type of interactions of individual peptide side chains with the MHC depend upon the geometry, charge distribution and hydrophobicity of the peptide binding groove. Wieczorek et al teach that prediction of peptide binding based upon bioinformatics algorithms (i.e., in silico predictions) yield false positive results. (See entire reference, especially page 2 at column 1 and the para spanning columns 1-2). (One of skill in the art was also aware that the presence of other residues besides those at anchor positions influence binding, independently and additively or subtractively).
Thus, the primary sequence of a peptide is not correlated to the functional property of binding to a MHC class I molecule, even when the peptide sequence comprises anchor amino acid residues for potential binding to the binding groove of a particular MHC class I molecule. Although experimental ranking schemes are available for predicting relative binding strengths of some MHC binding peptides and assays are available to test the binding of peptides to MHC, experimentation is not a rationale for providing adequate written description.
In addition, there is no representative number of species of such MHC class I heavy chains that with b2m will bind the peptides consisting of SEQ ID NO: 4-8 except for the aforementioned ones.
Neither the art nor the specification provide a representative number of species for each MHC class I molecule in the genus thereof, for longer than canonical length peptides given the closed nature of the peptide binding groove of classical MHC class I molecules (HLA-A, -B, -C), nor a structure/function relationship therefore for the functional property of binding. There are some longer peptides known for some of the Ib molecules (non-classical class I molecules); however, these are limited and not representative of the breadth of the species of peptide ligands, nor is there an absolute structure/function relationship between the primary sequence of such peptides and the Ib molecules to which they bind. This is also the case with peptides that are shorter than the length required to span the MHC-I peptide binding groove.
The specification discloses that the single chain fusion protein comprising the portions recited in instant base claim 1 comprises in some embodiments a peptide ligand that stabilizes the MHC-I protein prior to enzyme cleavage (page 2 at lines 24-30), i.e., the peptide ligand must possess the functional property of binding to a MHC-I with sufficient affinity to stabilize the complex.
With further regard to the fusion protein recited in dependent claim 9, there is no evidence of record that a peptide comprising, consisting of, or comprising a subsequence of one of SEQ ID NO: 4-8 can bind to any of the human or non-human MHC-I molecules recited in the claim (with the exception of a peptide consisting of one of SEQ ID NO: 4-8 that can bind to one of HLA-A*11:01, HLA-A*02, or HLA-A*01:01, as is noted above).
Therefore, it appears that the instant specification does not adequately disclose the breadth of the single chain fusion protein recited in the instant claims. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such single chain fusion proteins at the time the instant application was filed.
Applicant may potentially obviate this rejection by amending the claims to recite that the peptide ligand consists of the sequence represented by one of SEQ ID NO: 4, 5, 6, 7 and 8 and to recite the identity of the particular MHC class I heavy chain, including wherein the MHC-I heavy chain polypeptide comprises the amino acid sequence set forth in a particular SEQ ID NO.
Applicant’s arguments (of record on pages 9-11) in the amendment and response filed 2/18/26 are directed to the prior rejection of record. Those arguments that pertain to the instant rejection have been fully considered, but are not persuasive.
Despite the instant specification disclosing that the peptide ligand can include 4-30 amino acid residues, the art recognizes that this is not the case for MHC class I binding peptides; while MHC class II molecules have an open peptide binding groove that can accommodate peptides longer than the length required to span the peptide binding groove, the instant claims are drawn to a single chain MHC class I fusion protein. The art evidences that the ends peptide binding groove of MHC class I molecules are closed, length limiting the size of peptide that can bind therein.
Applicant argues that a person of ordinary skill in the art may create similar fusion proteins by referring to the description in the instant application. However, this argument is not persuasive, as experimentation is not a rationale for establishing adequate written description. Applicant is reminded that:
“Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
Applicant is also reminded that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (Ariad Phar., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011).
Applicant’s further argument that claim1 is amended to clarify the identity of the peptide ligand and therefore allegedly complies with the written description requirement is also not persuasive for the reasons enunciated above in this rejection.
5. No claim is allowed.
6. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the Examiner’s supervisor, 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.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641