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 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and the fee set forth in 37 C.F.R. § 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 C.F.R. § 1.114.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 08 July, 2026. Claims 31, 34-37, 40, and 43-51 are currently under examination.
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.
The previous rejection of claims 31, 34-37, 40, and 43-51 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out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention, is hereby withdrawn in response to Applicant’s amendment.
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 31, 34-37, 40, and 43-51 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).
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 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).
The amended claims are broadly directed toward a method of treating phenylketonuria (PKU) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a particle capable of infecting a target cell, wherein the particle comprises the following: i) an envelope protein; ii) a viral vector comprising a therapeutic cargo portion wherein the therapeutic cargo portion comprises the following: a) a phenylalanine hydroxylase (PAH) sequence comprising at least 95% percent identity with SEQ ID NO.: 1 or 2, wherein the PAH sequence is operatively controlled by both a hAAT promoter and a prothrombin enhancer. Claim 43 further references sequences comprising at least 95% identity with a prothrombin enhancer sequence (SEQ ID NO.: 5). Claim 51 references small RNA sequences comprising at least 95% identity with SEQ ID NOS.: 13 or 14. SEQ ID NOS.: 1 and 2 correspond to the hPAH gene (1,359 nt) and a codon-optimized version (1,359 nt), respectively. SEQ ID NO.: 5 corresponds to the prothrombin enhancer (120 nt). The genetic variation permitted by the claim language encompasses an inordinate number of nucleotide and polypeptide variants. However, the disclosure fails to provide any examples of modified PAH genes, promoters, or enhancer regions. The disclosure fails to identity which regions of any given sequence should be targeted for modification. SEQ ID NOS.: 1 and 2 encode phenylalanine hydroxylase (PAH). PAH comprises the following amino acid sequence:
MSTAVLENPG LGRKLSDFGQ ETSYIEDNCN QNGAISLIFS LKEEVGALAK VLRLFEENDV
NLTHIESRPS RLKKDEYEFF THLDKRSLPA LTNIIKILRH DIGATVHELS RDKKKDTVPW
FPRTIQELDR FANQILSYGA ELDADHPGFK DPVYRARRKQ FADIAYNYRH GQPIPRVEYM
EEEKKTWGTV FKTLKSLYKT HACYEYNHIF PLLEKYCGFH EDNIPQLEDV SQFLQTCTGF
RLRPVAGLLS SRDFLGGLAF RVFHCTQYIR HGSKPMYTPE PDICHELLGH VPLFSDRSFA
QFSQEIGLAS LGAPDEYIEK LATIYWFTVE FGLCKQGDSI KAYGAGLLSS FGELQYCLSE
KPKLLPLELE KTAIQNYTVT EFQPLYYVAE SFNDAKEKVR NFAATIPRPF SVRYDPYTQR
IEVLDNTQQL KILADSINSE IGILCSALQK IK (encoded by SEQ ID NOS.: 1 and 2). Changes in the nucleotide sequence may also alter the coding potential of the PAH protein. Single or multiple amino acid substitutions can alter the activity/function of PAH (Thórólfsson et al., 2003). Thórólfsson and colleagues reported that a single point mutation (C237R) resulted in reduced substrate affinity and positive binding cooperativity (see Fig. 1, p. 3421). The disclosure fails to describe the generation, isolation, and characterization of any PAH variants. The lack of support in the disclosure suggests Applicant did not contemplate making and using variant nucleotide and amino acid sequences.
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 breadth of the patent protection desired. Applicant argues the claim amendments overcome the rejection. This argument has been considered but is not deemed to be persuasive for the reasons set forth supra.
Scope of Enablement
Claims 31, 34-37, 40, and 43-51 stand rejected under 35 U.S.C. § 112(a), because the specification does not reasonably enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. The amended claims are broadly directed toward a method of treating phenylketonuria (PKU) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a particle capable of infecting a target cell, wherein the particle comprises the following: i) an envelope protein; ii) a viral vector comprising a therapeutic cargo portion wherein the therapeutic cargo portion comprises the following: a) a phenylalanine hydroxylase (PAH) sequence comprising at least 95% percent identity with SEQ ID NO.: 1 or 2, wherein the PAH sequence is operatively controlled by both a hAAT promoter and a prothrombin enhancer. The disclosure provides a limited number of working embodiments involving specific retroviral constructs with specific promoters and liver-specific enhancers (see Fig. 3). These constructs appeared to be effective at treating PKU in a murine model. However, this data could not be directly extrapolated to clinical efficacy.
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 is considerable and encompasses the utilization of any viral vector/particle for the treatment/prevention of PKU. However, the claims fail to identify the salient characteristics of any given viral vector. What type of viral vector is being employed (e.g., adeno-associated virus (AAV); adenovirus (Ad); retrovirus; lentivirus; or herpesvirus). What type of vector backbone is employed and how is the vector targeted to the desired tissue type? The choice of viral vector for clinical use depends upon several factors including the efficiency and duration of transgene expression, stability of the vector, the ease of production, toxicity, and safety.
2) The specification fails to provide adequate guidance pertaining to the identification of suitable PAH variants that would provide therapeutic effects. The PAH coding sequence is approximately 1,359 nucleotides in length. The genetic variation permitted by the claim language encompasses an inordinate number of nucleotide and polypeptide variants. However, the disclosure fails to provide any examples of modified PAH genes, promoters, or enhancer regions. The disclosure fails to identity which regions of any given sequence should be targeted for modification. SEQ ID NOS.: 1 and 2 encode phenylalanine hydroxylase (PAH). PAH comprises the following amino acid sequence:
MSTAVLENPG LGRKLSDFGQ ETSYIEDNCN QNGAISLIFS LKEEVGALAK VLRLFEENDV
NLTHIESRPS RLKKDEYEFF THLDKRSLPA LTNIIKILRH DIGATVHELS RDKKKDTVPW
FPRTIQELDR FANQILSYGA ELDADHPGFK DPVYRARRKQ FADIAYNYRH GQPIPRVEYM
EEEKKTWGTV FKTLKSLYKT HACYEYNHIF PLLEKYCGFH EDNIPQLEDV SQFLQTCTGF
RLRPVAGLLS SRDFLGGLAF RVFHCTQYIR HGSKPMYTPE PDICHELLGH VPLFSDRSFA
QFSQEIGLAS LGAPDEYIEK LATIYWFTVE FGLCKQGDSI KAYGAGLLSS FGELQYCLSE
KPKLLPLELE KTAIQNYTVT EFQPLYYVAE SFNDAKEKVR NFAATIPRPF SVRYDPYTQR
IEVLDNTQQL KILADSINSE IGILCSALQK IK (encoded by SEQ ID NOS.: 1 and 2). Changes in the nucleotide sequence may also alter the coding potential of the PAH protein. Single or multiple amino acid substitutions can alter the activity/function of PAH (Thórólfsson et al., 2003). Thórólfsson and colleagues reported that a single point mutation (C237R) resulted in reduced substrate affinity and positive binding cooperativity (see Fig. 1, p. 3421).
3) The disclosure fails to provide adequate guidance with respect to the transduction frequency and transgene expression levels of any given viral vector. Transduction efficiencies can vary widely depending upon the LTRs, promoters, enhancers, and other regulatory and structural elements employed. The disclosure fails to provide adequate guidance about these efficiencies in the various cell targets (e.g., hepatic, muscle, epithelial, endothelial, neural, etc.).
4) The disclosure only provides a limited working embodiment involving a specific lentiviral/retroviral construct in a murine model. However, this limited working embodiment is insufficient to support the full breadth of protection desired, particularly with respect to in utero gene therapy. Intrauterine fetal gene therapy suffers from a number of limitations including oncogenesis, genetic mutation transfer from mother to child, and fetal disruption. Furthermore, non-viral vectors appear to be more advantageous than viral vectors because of safety and usability profiles (Peddi et al., 2022).
5) The state-of-the-art teaches that human PKU gene therapy has been problematic and unpredictable, despite encouraging results in murine models (Grisch-Chan et al., 2019; Lichter-Konecki and Vockley, 2019). As Grisch-Chan and colleagues concluded, while some technologies have proven therapeutic in the PKU mouse model, nevertheless, they are still at the developmental level and need to be improved for clinical efficacy. Moreover, Lichter-Konecki and Vockley note that only two treatments are currently available for PAH deficiency; a low phenylalanine diet or cofactor therapy. At the time of filing, there were no clinically approved gene therapy approaches for the treatment of PAH deficiency.
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 argues the claim amendments overcome the rejection. This argument has been considered but is not deemed to be persuasive for the reasons set forth supra.
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, Michael Allen, Ph.D., can be reached at (571) 270-3497. 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 27 September, 2026
