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
The amendment file don 9-19-2025 is acknowledged. Claims 1-6, 13, 15-19 and 26-30 have been amended. Claims 31-34 have been added. Claims 1-6, 8-9, 12-13, 15-19 and 26-34 are pending. Claims 12-13, 15-19, 26-30 and 32-33are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-6, 8-9 and 31-32 are currently under examination.
Information Disclosure Statement
The Information Disclosure Statements filed on 11-19-2024, 9-19-2025 and 10-22-2025 have been considered. Initialed copies are attached hereto.
It should be noted that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Declaration
The Declarations by Nicolas R. Waterfield under 37 C.F.R. 1.132 and 37 C.F.R. 1.130(A) both filed on 9-19-2025 have been fully considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see pages 20 and 40). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
It should be noted that the cited occurrences of improper use are only exemplary and Applicant should review the entire specification to correct any other improper use of trademarks.
Claim Objections Maintained
The objection to claims 1 and 3-5 for reciting claim language drawn to non-elected inventions is maintained as said claim are not allowable.
Claim Rejections Withdrawn
The rejection of claim 1 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for lacking proper antecedent basis for the limitation "the leader sequence" in lines 5 and 9 is withdrawn in light of the amendment thereto.
The rejection of claim 2 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for lacking proper antecedent basis for the limitation "the leader sequence" in line 1 is withdrawn in light of the amendment thereto.
The rejection of claim 4 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for lacking proper antecedent basis for the limitation "the PVC effector" in line 1 is withdrawn in light of the amendment thereto.
The rejection of claim 5 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being rendered vague and indefinite by the use of the phrase “…comprises an amino acid sequence of one or more sequence selected from SEQ ID NO:1 – SEQ ID NO:46.” is withdrawn in light of the amendment thereto
The rejection of claim 5 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for lacking proper antecedent basis for the limitation "the PVC effector" in line 1 is withdrawn in light of the amendment thereto.
The rejection of claim 6 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for lacking proper antecedent basis for the limitation "the leader sequence" in line 1 is withdrawn in light of the amendment thereto.
The rejection of claims 1-6 and 8-9 under 35 U.S.C. 102(a)(1) as being anticipated by Vlisidou et al. (BioRxiv, pages 1-38. February 15, 2019 – IDS filed on 11-23-2021) is withdrawn.
Claim Rejections Maintained
35 USC § 112
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 1-6, 8-9 and 31-32 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 for the reasons set forth in the previous Office action in the rejection of claims 1-6 and 8-9. 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.
Applicant argues:
1. The Examples section made use of the "leader sequence" from the effector protein "Pnf', said leader sequence having a sequence of SEQ ID NO: 78.
2. At least six additional PVC effector leader sequences were also demonstrated to provide for packaging of a heterologous payload, else a modified payload. Sequence analysis outlined in the application shows that these exemplified "leader sequences" are at (or close to being) at maximal sequence diversity amongst the various PVC effector leader sequences. Therefore, the PVC effector leader sequences chosen for experimental exemplification are representative of the genus as a whole.
3. The Examples demonstrate the effective packaging of Cre-recombinase (or other heterologous payloads) into a PVC Needle Complex utilizing the “leader peptides” with the sequence of SEQ ID NO:71, 50, 68, 76 and 92 and thus demonstrate the utility of “leader sequences” showing greater sequence diversity.
4. The claims that recite % identity language still require that the claimed sequence is a "PVC effector leader sequence" by virtue of the claim language.
Applicant’s arguments have been fully considered and deemed non-persuasive.
With regard to Points 1-4, the instant claims are not limited to PVC effector leader sequences with the sequence of SEQ ID NO:71, 50, 68, 76 or 92. Claims 1-2, 6, 8-9 and 31-32 have no limitation regarding sequence are claimed purely by function. As set forth in the rejection the describing of a biological entity by their functions was addressed in the Centocor decision (CENTOCOR ORTHO BIOTECH, INC. v ABBOTT LABORATORIES (Fed Cir, 2010-1144, 2/23/2011)). In said case the court stated”
To satisfy the written description requirement, "the applicant must 'convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention,' and demonstrate that by disclosure in the specification of the patent." Carnegie Mellon Univ. v. Hoffmann-La Roche Inc., 541 F.3d 1115, 1122 (Fed. Cir. 2008) (quoting Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64 (Fed. Cir. 1991)). Assessing such "possession as shown in the disclosure" requires "an objective inquiry into the four corners of the specification." Ariad, 598 F.3d at 1351. Ultimately, "the specification must describe an invention understandable to [a person of ordinary skill in the art] and show that the inventor actually invented the invention claimed." Id. A "mere wish or plan" for obtaining the claimed invention is not adequate written description. Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1566 (Fed. Cir. 1997).
Moreover, even where the claims recite some limitation with regard to sequence, the encompassed PVC effector leader sequences constitute an extremely large genus. For example, the elected invention of SEQ ID NO:78 as recited in claim 3 encompasses 2.5 x 106 substitution variants. Given that said “variants” also include deletion and insertional mutants the number of variants encompasses by sequences “having at least 90% sequence identity” with SEQ ID NO:78 is even larger. The variants based on “derivatives” of SEQ ID NO:32 as set forth in claims 4 and 5, is even larger since there is no limitation with regard to what constitutes a “derivative”. Consequently, the limited number of PVC effector leader sequences that have been demonstrated to have the claimed biological activity is not deemed to be representative of the claimed genus. Consequently, proper written description requirements as set forth under 35 USC § 112, first paragraph is lacking.
The instant claims are drawn to the use of PVC effector leader sequences to package a payload (e.g. polypeptide, nucleic acid or combination thereof) to which it is fused into a Photorhabdus Virulence Cassettes (PVC) Needle complex wherein the PVC effector leader sequence/payload fusion does not comprise a wild-type PVC effector protein. Said claims optionally encompass PVC effector leader sequences that: comprise residues 1-50 of a PVC effector (claim 2); that have at least 90% sequence identity to SEQ ID NO:78 (claim 3); or are “derived” from a PVC effector that comprises the amino acid sequence of SEQ ID NO:32 (claims 4 and 5). It should be noted that there is no limitation with regard to the PVC effector leader sequence in claims 1-2, 6, 8-9 and 31-32.
To fulfill the written description requirements set forth under 35 USC § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which share a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. To adequately describe the claimed genus of PVC effector leader sequences, Applicant must adequately describe the actual sequences of the PVC effector leader sequences as well as the variant sequences of SEQ ID NO:78 that have the ability to package a heterologous payload into in a PVC needle complex.
The specification, however, does not disclose distinguishing and identifying features of a representative number of members of the genus of PVC effector leader sequences to which the claims are drawn, such as a correlation between the structure (sequence) of a given PVC effector leader sequence and its recited function (i.e. having the ability to package a payload into a PVC Needle complex) so that the skilled artisan could immediately envision, or recognize at least a substantial number of members of the claimed genus neurotoxins. The specification is limited to the disclosure of a single PVC effector leader sequence (i.e. SEQ ID NO:78 which corresponds to residues 1-50 of the PAU_03332 effector) with the claimed structure and biological characteristics. Disclosure of other recombinant PVC effector leader sequences is generalized and prophetic in nature. It should be noted that the specification discloses leader sequences with the amino acid sequences of SEQ ID NO:47-92 which corresponds to amino acids 1-50 of the PVC effectors with the amino acid sequences of SEQ ID NO:1-46, respectively. However, only the PVC effector leader sequence of SEQ ID NO:78 was reduced to practice. Moreover, the specification is silent with regard to any variants of SEQ ID NO:78 that have the claimed biological characteristics.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed' ”. The courts have decided:
The purpose of the “written description” requirement is broader than to merely explain how to “make and use”; the applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the “written description” inquiry, whatever is now claimed.
See Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991). Furthermore, the written description provision of 35 USC § 112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
MPEP 2163.02 further states, “[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by 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); Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); 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"). Moreover, because the claims encompass a genus of variant species, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Additionally, MPEP 2163 states:
"A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)”
And:
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Bowie et al (Science, 1990, 257:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function, carry out the instructions of the genome and perform biological functions. Bowie et al. further teach that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex. (column 1, page 1306). Bowie et al further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three-dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions (column 2, page 1306). Likewise, Skolnick et al. demonstrates that the art is unpredictable. Skolnick et al. (Trends in Biotechnology 18: 34-39, 2000) discloses the skilled artisan is well aware that assigning functional activities for any particular protein or protein family based upon sequence homology is inaccurate, in part because of the multifunctional nature of proteins (see, e.g., the abstract; and page 34, Sequence-based approaches to function prediction). Even in situations where there is some confidence of a similar overall structure between two proteins, only experimental research can confirm the artisan's best guess as to the function of the structurally related protein (see, in particular, the abstract and Box 2). Thus, one skilled in the art would not accept the assertion, which is based only upon an observed similarity in amino acid sequence that a variant of a given polypeptide would necessarily bind to a given antibody. The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al (J. of Cell Bio. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Molecular and Cellular Biology, 1988, 8:1247-1252) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein. Clearly, proteins with a sequence variant to the a wild-type protein that have enhanced functional characteristics could not be predicted. Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2). Clearly, given not only the teachings of Bowie et al., Lazar et al. and Burgess et al. but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the variants a given PVC leader sequences with the claimed biological characteristics cannot be predicted. Reasonable correlation must exist between structure and function.
Moreover, the describing of a biological entity by their functions was addressed in the Centocor decision (CENTOCOR ORTHO BIOTECH, INC. v ABBOTT LABORATORIES (Fed Cir, 2010-1144, 2/23/2011)). In said case the court stated”
To satisfy the written description requirement, "the applicant must 'convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention,' and demonstrate that by disclosure in the specification of the patent." Carnegie Mellon Univ. v. Hoffmann-La Roche Inc., 541 F.3d 1115, 1122 (Fed. Cir. 2008) (quoting Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64 (Fed. Cir. 1991)). Assessing such "possession as shown in the disclosure" requires "an objective inquiry into the four corners of the specification." Ariad, 598 F.3d at 1351. Ultimately, "the specification must describe an invention understandable to [a person of ordinary skill in the art] and show that the inventor actually invented the invention claimed." Id. A "mere wish or plan" for obtaining the claimed invention is not adequate written description. Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1566 (Fed. Cir. 1997).
The court further opined that Centocor's suggestion
that our decision in Noelle and the PTO written description guidelines support the view that fully disclosing the human TNF-α protein provides adequate written description for any antibody that binds to human TNF-α. That suggestion is based on an unduly broad characterization of the guidelines and our precedent.
The court concluded that
While our precedent suggests that written description for certain antibody claims can be satisfied by disclosing a well-characterized antigen, that reasoning applies to disclosure of newly characterized antigens where creation of the claimed antibodies is routine. Claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described.
Therefore, because the art is unpredictable, in accordance the MPEP and established case law, the description of biological function is not deemed representative of the genus recombinant neurotoxins with the claimed biological characteristics. Consequently, only the PVC leader sequence of SEQ ID NO:78, but not the full breadth of the instant claims meets the written description provision of 35 USC 112, first paragraph.
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.
The rejection of claim 3 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for lacking proper antecedent basis for the limitation "the leader sequence" in line 1 is maintained for reasons of record. It should be noted that Applicant did not address this rejection in their response.
New Grounds of Rejection
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 4 and 5 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.
Claim 4 is rendered vague and indefinite by the use of the phrase “…the PVC effector leader sequence is derived from a PVC effector…”. It is unclear what is meant to be engendered by the term “derived”. Is the leader sequence merely a part of the PVC effector or is it altered in some way? As written, it is impossible to determine the metes and bounds of the claimed invention.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ROBERT A ZEMAN/Primary Examiner, Art Unit 1645 January 12, 2026