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 .
Status of the Claims
Acknowledgement is hereby made of receipt and entry of the communication filed 30 December, 2025. Claims 1, 3, 4, 7, 12, 21, 23, 27, 31, 37, 45, 69, 72, 86, 87, 89, 91, and 109 are pending in the instant application.
37 C.F.R. § 1.84
The drawings filed 30 December, 2025, have been reviewed and are acceptable except where noted. In particular, Fig. 23 is objected to because it is still illegible (see the amino acid sequence set forth). Corrected drawing sheets in compliance with 37 C.F.R. § 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 C.F.R. § 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 72, 73, and 105 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out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention, is hereby withdrawn in response to Applicant’s amendment.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
Amended claims 1, 3, 4, 7, 12, 21, 23, 27, 31, 37, 45, 69, 72, 86, 87, 89, 91, and 109 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 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 directed toward a recombinant protein comprising from N-terminus to C-terminus, an N-terminal stabilizing domain comprising at least 95% amino acid sequence identity to SEQ ID NO.: 2 or 3, an optional linker region, and a heterologous protein domain. Claims 86, 87, and 89 are directed toward nucleic acids encoding the fusion protein and a kit comprising said fusion protein. Claims 91 and 109 reference methods of using said fusion protein to amplify target nucleic acids in a sample and to express the fusion protein of interest.
The amended claims still encompass a large genus of HP47 N-terminal stabilizing protein mutants. HP47 is encoded by SEQ ID NO.: 2 and contains the following amino acid sequence: PRGVDPSRKE NHLSDEDFKA VFGMTRSAFA NLPLWKQQNL KKEKGLF47. SEQ ID NO.: 3 contains an additional Met residue at the amino terminus. Just ~5% amino acid sequence variation would encompass upwards of ~2 x 107 variant HP47 proteins.1 This calculation assumes that any of the 20 naturally-occurring amino acids may be used and that said amino acid substitutions may be introduced anywhere within the HP47 sequence. However, the disclosure fails to provide sufficient guidance directing the skilled artisan toward any particular amino acid. The disclosure also fails to provide sufficient guidance with respect to the functional properties of HP47. There is no discussion about the molecular determinants modulating the stabilizing activity of HP47. A limited number of mutants were identified in the specification, however, these are insufficient to put Applicant in possession of the full genus of HP47 variants.
Claim 45 is also directed toward an inordinate number of Bst polymerase variants (a protein comprising at least 95% amino acid sequence identity with SEQ ID NO.: 19). This sequence corresponds to a Bst polymerase fragment and has the following amino acid sequence: MHHHHGHHHH PRGVDPSRKE NHLSDEDFKA VFGMTRSAFA NLPLWKQQNL KKEKGLFGSG SAAAPKMAFT LADRVTEEML ADKAALVVEV VEENYHDAPI VGIAVVNEHG RFFLRPETAL ADPQFVAWLG DETKKKSMFD SKRAAVALKW KGIELCGVSF DLLLAAYLLD PAQGVDDVAA AAKMKQYEAV RPDEAVYGKG AKRAVPDEPV LAEHLVRKAA AIWELERPFL DELRRNEQDR LLVELEQPLS SILAEMEFAG VKVDTKRLEQ MGKELAEQLG TVEQRIYELA GQEFNINSPK QLGVILFEKL QLPVLKKTKT GYSTSADVLE KLAPYHEIVE NILHYRQLGK LQSTYIEGLL KVVRPDTKKV HTIFNQALTQ TGRLSSTEPN LQNIPIRLEE GRKIRQAFVP SESDWLIFAA DYSQIELRVL AHIAEDDNLM EAFRRDLDIH TKTAMDIFQV SEDEVTPNMR RQAKAVNFGI VYGISDYGLA QNLNISRKEA AEFIERYFES FPGVKRYMEN IVQEAKQKGY VTTLLHRRRY LPDITSRNFN VRSFAERMAM NTPIQGSAAD IIKKAMIDLN ARLKEERLQA HLLLQVHDEL ILEAPKEEME RLCRLVPEVM EQAVTLRVPL KVDYHYGSTW YDAK644.
Thus, even 5% amino acid sequence variation would encompass upwards of 32 amino acid insertions, deletions, or substitutions anywhere within the polymerase which corresponds to ~7 x 1097 variant sequences.2 However, the disclosure fails to provide sufficient guidance directing the skilled artisan toward any particular amino acid. The disclosure also fails to provide sufficient guidance with respect to the functional properties of the Bst polymerase. There is no discussion about the molecular determinants modulating the various activities of Bst.
Moreover, the generation of polymerase mutants with improved properties can be challenging (Piotrowski et al., 2019; Oscorbin and Filipenko, 2023; Li et al., 2023). Piotrowski and colleagues screened thousands of DNA polymerase I mutants and were only able to identify a single mutant with increased activity. Oscorbin and Filipenko reviewed some of the biochemical properties of Bst polymerase including strand displacement, fidelity, replication slippage, terminal transferase activity, reverse transcriptase activity, exonuclease activity, thermal stability, DNA polymerase activity, and processivity. The authors noted that Bst is relatively poorly studied as compared to other DNA polymerases. Finally, Li and colleagues used molecular modeling to identify suitable mutational target sites in Bst. However, only a limited number of mutants were identified with enhanced activity, once again demonstrating the challenges associated with generating Bst polymerase mutants with enhanced characteristics. The disclosure only provides a limited number of mutants with enhanced DNA polymerase activity. However, this number was insufficient to put Applicant in possession of the full genus of Bst mutants.
Accordingly, when all the aforementioned factors are considered in toto, the skilled artisan would reasonably conclude that Applicants were not in possession of the claimed invention at the time of filing.
Applicant traverses and submits that the specification supports the claimed genus of HP47 N-terminal stabilizing domains. In particular, it was taught that this region forms a zwitterionic alpha helix containing oppositely charged surfaces that stabilizes the fusion partner (see paragraphs [0072] and [00171]-[00173]). Paragraph [0072] notes that the terminal forty-seven amino acids of the C-terminal domain of the Gallus gallus villin protein increase the fusion partner’s solubility and thermostability. The remaining paragraphs describe mutagenesis studies involving this stabilizing protein wherein eight mutants were generated. Four mutants displayed no enhanced activity whereas four other mutants showed increased thermostability. With respect to the polymerase sequence variation, Applicant submits that no functional properties were cited.
As set forth supra, the claimed genus encompasses upwards of ~2 x 107 variant HP47 proteins. The limited number of mutants is insufficient to support the full breadth of the patent protection desired, particularly considering the unpredictability associated with these mutations. With respect to the Bst polymerase variants, the claims still require a functional polymerase. However, the claims encompass an inordinate number of variants fail to receive support in the specification as previously set forth. Accordingly, the rejection is proper and maintained.
Action Is Final
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 C.F.R. § 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 extension fee pursuant to 37 C.F.R. § 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.
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
29 April, 2026
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.
2 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.
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