Detailed Office 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 .
37 C.F.R. § 1.114
A request for continued examination under 37 C.F.R. § 1.114, including the fee set forth in 37 C.F.R. § 1.17(e), was filed 30 June, 2025, in this application after final rejection. Since this application is eligible for continued examination under 37 C.F.R. § 1.114, and the fee set forth in 37 C.F.R. § 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 C.F.R. § 1.114.
Status of the Claims
Acknowledgement is hereby made of receipt and entry of the communication filed 23 May, 2025. Claims 28-33 and 35-48 are pending in the instant application.
35 U.S.C. § 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.
Claims 28-33 and 35-48 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. Two separate requirements are set forth under this statute: (1) the claims must set forth the subject matter that applicants regard as their invention; and (2) the claims must particularly point out and distinctly define the metes and bounds of the subject matter that will be protected by the patent grant.
The claims are directed toward a process of immunizing a subject, comprising administering to said subject a three-dimensional protein structure comprising a multimeric self-assembling nanocage, wherein said nanocage is composed of a plurality of protein substructures comprising a linker and capture sequence on the N-terminus, wherein said substructures comprise an amino acid sequence that is 90% or greater identical to any one of SEQ ID NOS.: 1-6 and a capture sequence that is 90% or greater identical to any one of SEQ ID NO.: 8 or 9, or a capture sequence comprising biotin or avidin, and a target protein comprising a tag that is complementary to the capture sequence and capable of forming a covalent bond with the capture sequence of SEQ ID NO.: 8 or 9, or a noncovalent bond with avidin or biotin that displays a binding dissociation constant (Kd) of 10-12M or lower.
The claims suffer from a number of deficiencies. First, the method is confusing because it appears to be missing some characteristic immunization steps. Typically, an immunization regimen involves the preparation of the immunogen (including the addition of one or more specific adjuvants), administration of the immunogen to one or more sites (e.g., mucosal) at certain intervals, and the measurement of certain parameters (e.g., neutralizing antibody responses) associated with a therapeutically acceptable outcome. Second, the claims are also vague and indefinite for failing to identify the target disease. The term immunize implies the development of an immune response that provides a positive therapeutic outcome against a particular infectious disease or cancer. However, it is not readily manifest what type of disease or infection will be targeted by the target protein. Further adding to the confusion with respect to disease treatment and prevention, the specific target proteins of claim 43 are proteins whose normal functions are required by the host. Thus, it is not readily manifest how generating an immune response against these target proteins would lead to a therapeutic outcome. For example, the PABP protein is required for the addition of the poly(A) tail to mRNA and may also protect it. In the absence of PABP, mRNA is rapidly degraded. Thus, it is not readily manifest why the skilled artisan would induce an immune response against this protein.
35 U.S.C. § 112(a)
The following is a quotation 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.
Written Description
Claims 28-33 and 35-48 stand rejected under 35 U.S.C. § 112(a), 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, at the time the application was filed, had possession of the claimed invention. Amgen, Inc. v. Sanofi, 872 F.3d 1367, 124 U.S.P.Q.2d 1354 (Fed. Cir. 2017). AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 111 U.S.P.Q.2d 1780 (Fed. Cir. 2014). Univ. of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 920, 69 U.S.P.Q.2d 1886, (Fed. Cir. 2004). Enzo Biochem, Inc. v. Gen-Probe, Inc., 296 F.3d 1316, 63 U.S.P.Q.2d 1609, (Fed. Cir. 2002). Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 U.S.P.Q.2d 1398, (Fed. Cir. 1997). Fiers v. Revel Co., 984 F.2d 1164, 25 U.S.P.Q.2d 1601, (Fed. Cir. 1993). Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 18 U.S.P.Q.2d 1016, (Fed. Cir. 1991). In re Rasmussen, 650 F.2d 1212, 211 U.S.P.Q. 323 (C.C.P.A. 1981). In re Wertheim, 541 F.2d 257, 191 U.S.P.Q. 90 (C.C.P.A. 1976).
As previously set forth, the crux of the statutory requirement governing written description is whether one skilled in the art, familiar with the practice of the art at the time of the filing date, could reasonably have found the later claimed invention in the specification as filed. In re Kaslow, 707 F.2d 1366, 1375, 217 U.S.P.Q. 1089, 1096 (Fed. Cir. 1983). In re Wilder, 736 F.2d 1516, 1520 222 U.S.P.Q. 349, 372 (Fed. Cir. 1984, cert. denied, 469 U.S. 1209 (1985). Texas Instruments, Inc. v. International Trade Comm’n, 871 F.2d 1054, 1063, 10 U.S.P.Q.2d 1257, 1263 (Fed. Cir. 1989). Moreover, the courts have stated that the evaluation of written description is highly fact-specific, and that broadly articulated rules are inappropriate. In re Wertheim, 541 F.2d 257, 263, 191 U.S.P.Q. 90, 97 (C.C.P.A. 1976). In re Driscoll, 562 F.2d 1245, 1250, 195 U.S.P.Q. 434, 438 (C.C.P.A. 1977). It is also important to remember that the true issue in question is not whether the specification enables one of ordinary skill in the art to make the later claimed invention, but whether or not the disclosure is sufficiently clear that those skilled in the art will conclude that the applicant made the invention having the specific claim limitations. Martin v. Mayer, 823 F2d 500, 505, 3 U.S.P.Q.2d 1333, 1337 (Fed. Cir. 1987).
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor has possession of the claimed invention. See, e.g., Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116. 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. American Airlines, Inc., 107 F.3d 1565, 1572, 41 U.S.P.Q.2d 1961, 1966 (Fed. Cir. 1997). The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence. A lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process. Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 U.S.P.Q.2d 1895, 1905 (Fed. Cir. 1996).
Determination of adequate written description requires the Examiner to read and analyze the specification for compliance with 35 U.S.C. § 112(a). In particular, each claim should be analyzed to determine its broadest reasonable interpretation consistent with written description. Each claim should be evaluated to determine if sufficient structures, acts, or functions are recited to make clear the scope and meaning of the claim, including the weight to be given the preamble. The entire application should be reviewed including the specific embodiments, figures, and sequence listings, to understand how applicant provides support for the various features of the claimed invention. The analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated that the inventor was in possession of the claimed invention. Such a review is conducted from the standpoint of one of ordinary skill in the art at the time the application was filed (see, e.g., Wang Labs., Inc. v. Toshiba Corp., 993 F.2d 858, 865, 26 USPQ2d 1767, 1774 (Fed. Cir. 1993)) and should include a determination of the field of the invention and the level of skill and knowledge in the art. Finally, the Examiner should determine whether there is sufficient written description to inform a skilled artisan that the inventor was in possession of the claimed invention as a whole at the time of filing.
The amended claims are broadly directed toward a method of immunizing a subject, comprising administering to said subject a three-dimensional protein structure comprising a multimeric self-assembling nanocage, wherein said nanocage is composed of a plurality of protein substructures comprising a linker and capture sequence on the N-terminus, wherein said substructures comprise an amino acid sequence that is 90% or greater identical to any one of SEQ ID NOS.: 1-6 and a capture sequence that is 90% or greater identical to any one of SEQ ID NO.: 8 or 9, or a capture sequence comprising biotin or avidin, and a target protein comprising a tag that is complementary to the capture sequence and capable of forming a covalent bond with the capture sequence of SEQ ID NO.: 8 or 9, or a noncovalent bond with avidin or biotin that displays a binding dissociation constant (Kd) of 10-12M or lower.
SEQ ID NOS.: 1-6 are directed toward I3-01 self-assembling nanocage proteins. They vary in length between 201-207 amino acids. The amino acid sequence of SEQ ID NO.: 1 is set forth as follows:
MEELFKKHKIVAVLRANSVEEAKKKALAVFLGGVHLIEITFTVPDADTVIKELSFLKEMGAIIGAGTVTSVEQCRKAVESGAEFIVSPHLDEEISQFCKEKGVFYMPGVMTPTELVKAMKLGHTILKLFPGEVVGPQFVKAMKGPFPNVKFVPTGGVNLDNVCEWFKAGVLAVGVGSALVKGTPVEVAEKAKAFVEKIRGCTEHM, I3-01 (205 aa). SEQ ID NOS.: 8 and 9 are directed toward SpyCatcher and SnoopCatcher proteins of 108 and 113 amino acids, respectively. The amino acid sequence of SEQ ID NO.: 8 is set forth as follows: MGSSHHHHHHGSGDSATHIKFSKRDEDGKELAGATMELRDSSGKTISTWISDGQVKDFYLYPGKYTFVETAAPDGYEVATAITFTVNEQGQVTVNGKATKGDAHIGVD.
As previously set forth, the claims encompass an inordinate number of I3-01 and SpyCatcher/SnoopCatcher variants. For example, just 10% genetic unrelatedness would include upwards of 20 different amino acid substitutions, insertions, or deletions at any point in the sequence and encompass ~1 x 1055 variant I3-01 sequences and ~4 x 1030 variant SpyCatcher/SnoopCatcher sequences.1 However, the disclosure fails to provide adequate guidance with respect to the molecular determinants modulating I3-01 nanocage self-assembly, as well as, the other functional properties of the molecule. Which amino acids should be targeted for modification without adversely affecting the functional properties of I3-01? The disclosure also fails to provide adequate guidance with respect to the molecular determinants modulating SpyCatcher/SnoopCatcher function. Which amino acids can be modified without adversely impacting the activities SpyCatcher/SnoopCatcher? Amendment of the claim language to reference the specific I3-01 protein substructures (e.g., one of SEQ ID NOS.: 1-6) and specific SpyCatcher/SnoopCatcher sequences (e.g., SEQ ID NO.: 8 or 9) would be acceptable.
The claims are also broadly directed toward an immunization regimen using any sundry target protein wherein said protein comprises a tag, wherein said tag is complementary to the capture sequence. The term immunization typically encompasses the generation of an immune response that provides a therapeutic or prophylactic response against an invading pathogen or cancer cell. However, the claims fail to identify any particular infectious agent or disease that should be targeted. While a limited number of proteins were set forth in claim 43, these fail to address this deficiency. For example, the PABP protein is required for the addition of the poly(A) tail to mRNA and may also protect it from degradation. In the absence of PABP, mRNA is rapidly degraded. Thus, it is not readily manifest why the skilled artisan would induce an immune response against this protein.
Accordingly, when all the aforementioned factors are considered in toto, the skilled artisan would reasonably conclude that Applicant was not in possession of a sufficient number of species to support the full claim breadth sought. Applicant submits the claim amendments directed toward the I3-01 and SpyCatcher/SnoopCatcher sequences provided, including upwards of 10% genetic variation, is sufficient to meet the written description requirement. It was further asserted that sufficient target proteins were set forth in claim 43. Since the specific structures were provided this would readily support the broader genuses.
Applicant’s arguments have been carefully considered but are not deemed to be persuasive for the reasons of record set forth supra. As noted in the analysis, the genus of I3-01 and SpyCatcher/SnoopCatcher variants encompasses an inordinate number of proteins. However, the disclosure fails to provide adequate guidance with respect to the identification of the molecular determinants modulating the functions of these various proteins. Accordingly, the skilled artisan cannot readily envisage which variants will have the desired properties and form stable nanocages for immunogen delivery. With respect to the SpyCatcher/SnoopCatcher sequences, absent evidence to the contrary, the skilled artisan cannot readily envisage which variants will retain binding activity to a target protein carrying a suitable tag (e.g., SpyTag or SnoopTag). Furthermore, the disclosure fails to adequately describe which diseases or infectious agents should be targeted. Applicant’s response failed to proffer any data or publications addressing these deficits. Applicant’s representative is invited to contact the Examiner to discuss suggested claim revisions.
Enablement
Claims 28-33 and 35-48 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 legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
1) The claim breadth with respect to the target of the immunization protocol is incredibly broad. The term immunization references the induction of a therapeutic or prophylactic response against a specific pathogen or disease. However, the claims fail to identify any suitable targets.
2) The claim breadth with respect to the target protein/immunogen employed in the immunization protocol is also incredibly broad. In order to immunize a host against any given disease or pathogen, suitable vaccine immunogens need to be identified. However, the claims fail to provide adequate guidance with respect to the identification of suitable immunogens. Adding to the confusion is the identification of normal cellular proteins as targets of the immunization protocol. For example, the PABP protein is required for the addition of the poly(A) tail to mRNA and may also protect it from degradation. In the absence of PABP, mRNA is rapidly degraded. Thus, it is not readily manifest why the skilled artisan would induce an immune response against this protein.
3) The disclosure fails to provide adequate guidance with respect to the correlates of protection for any given disorder. What is the nature, specificity, duration, and titer of the immune response required against any given target protein/immunogen to confer a therapeutic or protective outcome?
4) The disclosure fails to provide adequate guidance with respect to the generation of suitable nanocage immunogens and immunization regimens. In order to provide adequate immunity against a pathogen, suitable vaccine immunogens need to identified. Furthermore, suitable immunization parameters also need to be identified (e.g., immunogen formulation; site of immunization; utilization of adjuvants; length of prime-boosting regimen; identification of the immune response that correlates with protection in the subject; etc.).
5) Nanocage-based immunization protocols suffer from a number of limitations (Kim et al., 2023; previously cited) including the following: 1) Reproducibility of the manufacturing and scale-up processes can be challenging; 2) In vivo bioavailability often needs to be increased because protein nanocages are rapidly cleared from the body; 3) Immunity against the nanocage protein can lead to neutralization and rapid immune clearance of the nanocage immunogen; and, 4) Protein nanocage vaccines suffer from “original antigenic sin” which leads to insufficient immune responses against different strains of a pathogen.
6) The disclosure fails to provide any working embodiments wherein a specific disease or pathogen were targeted by the protein nanocage immunogen. No in vivo data was provided demonstrating that any given protein nanocage immunogen was capable of inducing a pathogen-specific immune response of sufficient specificity, titer, and duration that correlates with a positive therapeutic outcome.
Accordingly, when all the aforementioned factors are considered in toto, the skilled artisan would reasonably conclude that undue experimentation would be required to practice the claimed invention. Applicant’s representative is invited to contact the Examiner to discuss suggested claim revisions.
Correspondence
Any inquiry concerning this communication should be directed to Jeffrey S. Parkin, Ph.D., whose telephone number is (571) 272-0908. The Examiner can normally be reached Monday through Friday from 10:00 AM to 6:00 PM. A message may be left on the Examiner's voice mail service. 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 are unsuccessful, the Examiner's supervisor, Janet L. Andres, Ph.D., can be reached at (571) 272-0867. Direct general status inquiries to the Technology Center 1600 receptionist at (571) 272-1600.
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Respectfully,
/JEFFREY S PARKIN/Primary Examiner, Art Unit 1671 16 September, 2025
1 These calculations were performed as follows: TV=(NY)(X!)/(Y!)((X-Y-1)!), wherein, TV=the total number of variant sequences, N=the number of amino acids or nucleotides that can be substituted (i.e., if any of the 20 naturally occurring amino acids can be substituted, N=19; if any of the four naturally occurring nucleotides can be substituted, N=3), Y=the number of amino acids/nucleotides in the parent sequence that can be substituted (i.e., if the amino acid sequence is 100 aa in length and 10% genetic variation is allowed, Y=10 [100@10%]), and X=the total sequence length of the sequence of interest.