DETAILED 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 .
Claim Objections
Claim 93 is objected to because of the following informality: in step (d) “measure” should be – measured --.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 81, 84, 85, 88-92, 96, and 98-100 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Bruce et al. WO 2013/153359 A1 (hereafter “Bruce”).
Addressing claim 81, Bruce discloses a system (page 55, line 20 – page 56,
line 4), comprising:
a capture polynucleotide comprising a bilayer anchor moiety (see Figure 1 [1] and note the following on page 3, lines 30-33, “Fig. 1 shows an example schematic of the use of a helicase (labelled A) to control DNA movement through a lysenin nanopore (labelled B). 1) A ssDNA substrate with an annealed primer containing a cholesterol-tag (labelled D) is added to the cis side (labelled X) of the bilayer (labelled C). [italicizing by the Examiner]” The Examiner is construing “an annealed primer containing a cholesterol-tag (labelled D)“ as the claimed capture polynucleotide, and the cholesterol-tag as a bilayer anchor moiety. Also, on page 58, lines 30-32, “Annealed to this strand just after the 5OT leader is a primer containing a 3' cholesterol tag to enrich the DNA on the surface of the bilayer, and thus improve capture efficiency.”);
a target polynucleotide hybridized to the capture polynucleotide (see Figure 1 [1] and note the following on page 3, lines 30-33, “Fig. 1 shows an example schematic of the use of a helicase (labelled A) to control DNA movement through a lysenin nanopore (labelled B). 1) A ssDNA substrate with an annealed primer containing a cholesterol-tag (labelled D) is added to the cis side (labelled X) of the bilayer (labelled C). [italicizing by the Examiner]” The Examiner is construing “ssDNA substrate” as the claimed “a target polynucleotide”. Also, on page 38, line 25, “The target analyte is preferably a nucleotide, an oligonucleotide or a polynucleotide.”);
a helicase (see Figure 1 [1] and note the following on page 3, line 30, “Fig. 1 shows an example schematic of the use of a helicase (labelled A) . . . . [italicizing by the Examiner]” );
a polypeptide pore inserted into a membrane (see Figure 1 [1] and note the following on page 3, lines 30-33, “Fig. 1 shows an example schematic of the use of a helicase (labelled A) to control DNA movement through a lysenin nanopore (labelled B) [italicizing by the Examiner]. Also, not the following on page 8, line 7, “ SEQ ID NO: 2 shows the amino acid sequence of the lysenin monomer.”);
a generator adapted to provide a potential difference across the polypeptide pore (such a generator is implied by the following on page 4, lines1-2, “Under an applied voltage, the DNA substrate is captured by the nanopore via the leader section on the DNA The DNA is pulled through the pore under the force of the applied potential until a helicase, bound to the DNA, contacts the top of the pore, preventing further uncontrolled DNA translocation.”);
a detector adapted to measure an ionic current flowing through the polypeptide pore (such a detector is implied by the following on page 49, lines 28-30, “The measurement may be a transmembrane current measurement such as measurement of ionic current flowing through the pore.”); and
a processor programmed with instructions to characterize signals from fractional translocation of the target polynucleotide through the polypeptide pore (such a processor is implied by page 52, line 17, - page 54, line 21, which discusses how individual nucleotides may be identified based on current flows as they traverse the nanopore. Also, see page 22, line 30 to page 23, line 18, which discloses using specialized software and algorithms for sequencing.).
Addressing claim 84, for the additional limitation of this claim note the following on page 59, lines 10-11, “DNA polynucleotide (SEQ ID NO: 13 and 14) and Hel308 Mbu (SEQ ID NO: 15) were added to 50 μL of buffer (625 mM KCl, 100 mM Hepes pH 8.0, . . . . [italicizing by the Examiner]”
Addressing claim 851, as a first matter note that Applicant’s SEQ ID NO. 4 is as follows
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In three-letter code it as follows
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Bruce SEQ ID no. 15 (Methanococcoides burtonii) satisfies the additional limitation of claim 85 –
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Addressing claim 88, for the additional limitation of this claim see page 34,
line 35.
Addressing claim 89, for the additional limitation of this claim see page 58,
lines 11-14.
Addressing claim 90, the additional limitation of this claim is implied by the following on page 58, lines 31-35, “Annealed to this strand just after the SOT leader is a primer containing a 3' cholesterol tag to enrich the DNA on the surface of the bilayer, and thus improve capture efficiency. Electrical measurements were acquired from single wild-type lysenin (SEQ ID NO: 2) nanopores inserted in 1,2-diphytanoyl-glycero-3-phosphocholine lipid (DPhPC, Avanti Polar Lipids) bilayers. [italicizing by the Examiner]” Also, see Figure 1 and note the following on page 3, lines 30-34, “Fig. 1 shows an example schematic of the use of a helicase (labelled A) to control DNA movement through a lysenin nanopore (labelled B). 1) A ssDNA substrate with an annealed primer containing a cholesterol-tag (labelled D) is added to the cis side (labelled X) of the bilayer (labelled C). The cholesterol tag binds to the bilayer, enriching the substrate at the bilayer surface.”
Addressing claim 91, the additional limitation of this claim is implied by the following on page 58, lines 31-35, “Annealed to this strand just after the SOT leader is a primer containing a 3' cholesterol tag to enrich the DNA on the surface of the bilayer, and thus improve capture efficiency. Electrical measurements were acquired from single wild-type lysenin (SEQ ID NO: 2) nanopores inserted in 1,2-diphytanoyl-glycero-3-phosphocholine lipid (DPhPC, Avanti Polar Lipids) bilayers. [italicizing by the Examiner]” Also, see Figure 1 and note the following on page 3, lines 30-34, “Fig. 1 shows an example schematic of the use of a helicase (labelled A) to control DNA movement through a lysenin nanopore (labelled B). 1) A ssDNA substrate with an annealed primer containing a cholesterol-tag (labelled D) is added to the cis side (labelled X) of the bilayer (labelled C). The cholesterol tag binds to the bilayer, enriching the substrate at the bilayer surface.”
Addressing claim 92, for the additional limitation of this claim note the following on page 59, lines 2-4, “Single channel currents were measured on Axopatch 200B amplifiers (Molecular Devices) equipped with 1440A digitizers. [italicizing by the Examiner]”
Addressing claim 96, Bruce discloses a method for sequencing a target polynucleotide (see Bruce claim 37), comprising:
(a) inserting a polypeptide pore inserted into a membrane (this step is implied by see Figure 1 [1], which shows the product of this step, and by the following on page 3, lines 30-33, “Fig. 1 shows an example schematic of the use of a helicase (labelled A) to control DNA movement through a lysenin nanopore (labelled B) [italicizing by the Examiner]. Also, not the following on page 8, line 7, “ SEQ ID NO: 2 shows the amino acid sequence of the lysenin monomer.” );
(b) contacting the membrane with a solution comprising the target polynucleotide and a helicase (see Figure 1; page 3, lines 30-33; and page 47, lines 4-8);
(c) coupling a generator and a detector to the membrane (coupling a generator as in this step is implied by the following on page 4, lines1-2, “Under an applied voltage, the DNA substrate is captured by the nanopore via the leader section on the DNA The DNA is pulled through the pore under the force of the applied potential until a helicase, bound to the DNA, contacts the top of the pore, preventing further uncontrolled DNA translocation.” Coupling a detector as in this step is implied by the following on page 49, lines 28-30, “The measurement may be a transmembrane current measurement such as measurement of ionic current flowing through the pore.”), wherein the generator is adapted to provide a potential difference across the polypeptide pore and the detector is adapted to measure an ionic current flowing through the polypeptide pore (see again the passages just cited for “coupling a generator and a detector to the membrane”); and
(d) coupling a processor to the detector, wherein the processor is programmed with instructions to characterize signals from fractional translocation of the target polynucleotide through the polypeptide pore (this step is iml0ied by the following page 52, line 17, - page 54, line 21, which discusses how individual nucleotides may be identified based on current flows as they traverse the nanopore. Also, see page 22, line 30 to page 23, line 18, which discloses using specialized software and algorithms for sequencing.).
Addressing claim 98, for the additional limitation of this claim note the following on page 59, lines 10-11, “DNA polynucleotide (SEQ ID NO: 13 and 14) and Hel308 Mbu (SEQ ID NO: 15) were added to 50 μL of buffer (625 mM KCl, 100 mM Hepes pH 8.0, . . . . [italicizing by the Examiner]”
Addressing claim 99, for the additional limitation of this claim see page 34,
line 35.
Addressing claim 100, as for the limitation “a capture polynucleotide comprising a bilayer anchor moiety”, see Figure 1 [1] and note the following on page 3, lines 30-33, “Fig. 1 shows an example schematic of the use of a helicase (labelled A) to control DNA movement through a lysenin nanopore (labelled B). 1) A ssDNA substrate with an annealed primer containing a cholesterol-tag (labelled D) is added to the cis side (labelled X) of the bilayer (labelled C). [italicizing by the Examiner]” The Examiner is construing “an annealed primer containing a cholesterol-tag (labelled D)“ as the claimed capture polynucleotide, and the cholesterol-tag as a bilayer anchor moiety. Also, on page 58, lines 30-32, “Annealed to this strand just after the 5OT leader is a primer containing a 3' cholesterol tag to enrich the DNA on the surface of the bilayer, and thus improve capture efficiency.”
As for the claim 100 limitation “wherein the target polynucleotide is hybridized to a capture polynucleotide”, see Figure 1 [1] and note the following on page 3, lines 30-33, “Fig. 1 shows an example schematic of the use of a helicase (labelled A) to control DNA movement through a lysenin nanopore (labelled B). 1) A ssDNA substrate with an annealed primer containing a cholesterol-tag (labelled D) is added to the cis side (labelled X) of the bilayer (labelled C). [italicizing by the Examiner]” The Examiner is construing “ssDNA substrate” as the claimed “a target polynucleotide”. Also, on page 38, line 25, “The target analyte is preferably a nucleotide, an oligonucleotide or a polynucleotide.”
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 86 is rejected under 35 U.S.C. 103 as being unpatentable over Bruce.
Addressing claim 86, as a first matter note that Bruce meets all of the limitations of underlying clam 81. See the rejection of claim 81 above under 35 U.S.C 102(a)(2). Also, “a constriction zone” is defined by Applicant as follows, “A constriction zone is a location in the lumen of the pore where blockage by an analyte (e.g., a polynucleotide or nucleotide) affects a detectable signal produced by the pore.”2 See Applicant’s originally filed specification paragraph [0083].
As for the claim 86 limitation “. . . ., wherein the polypeptide pore comprises a constriction zone with a length no longer than five consecutive nucleotides…”, Bruce does not appear to provide enough information to clearly determine whether or not this limitation is met; however, Bruce does clearly disclose creating mutant lysenin monomer to alter one or more properties of the nanopore, such as sterics, charge, hydrogen bonding, pi stacking, and structure of the pore. See Bruce page 9, line 25 to page 11, line 2. Moreover, Bruce discloses altering the composition and/or structure of the nanopore in order to affect the interaction of the nanopore with the target analyte. See Bruce page 11, lines 3-19; and page 11, line 30 – page 12, line 8 (note especially, “If the one or more modifications are being made to improve polynucleotide capture, . . . . [italicizing by the Examiner]”). So, the additional claim 86 limitation is prima facie obvious as routine optimization of a known result effect variable.
7. Claim 87 is rejected under 35 U.S.C. 103 as being unpatentable over Bruce in view of Gundlach et al. US 2012/0055792 A1 (hereafter “Gundlach”).
Addressing claim 87, as a first matter note that Bruce meets all of the limitations of underlying clam 81. See the rejection of claim 81 above under 35 U.S.C 102(a)(2).
Bruce does not disclose wherein the polypeptide pore comprises a Mycobacterium smegmatis porin A (MspA) pore; in Bruce the pore is formed of mutant lysenin monomers. See Bruce page 9, lines 25-27.
Gundlach discloses MspA nanopores, systems that comprise these nanopores, and methods of using and making these nanopores. Such MspA nanopores may be used in a system for analyzing nucleic acids wherein the nanopore is in a lipid bilayer and the system is configured to electrophoretically translocate a nucleic acid molecule through the nanopore and monitor changes in current during the translocation. See in Gundlach paragraphs [0007], [0011], [0052], and [0055]-[0057]; and Figures 3A and 3B.
Barring evidence to the contrary, such as unexpected results, to substitute a MspA nanopore as taught by Gundlach for the nanopore in Bruce formed of mutant lysenin monomer is prima facie obvious as simple substitution of one known element (nanopore for nucleic acid analysis) for another to obtain predictable results. See MPEP 2143(I)(B).
Allowable Subject Matter
Claims 82, 83, 93-95, and 97 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
a) claim 82 requires the following underlined feature
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Applicant defines “full translation cycle” in originally filed specification paragraph [0059], which is reproduced below
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Neither Bruce nor other available prior art disclose such instructions.
b) clam 83 depends from allowable claim 82.
c) claim 93 requires the following underlined features “. . . .; (c) measuring at least two signals for at least one nucleotide of the target polynucleotide moving through the pore during a full translocation cycle of the helicase; and (d) sequencing the target polynucleotide using the at least two signals measure in step (c).
Neither Bruce nor other available prior art disclose such measuring during a full translocation cycle of the helicase.
d) clam 94 and 95 each depend from allowable claim 93.
e) claim 97 requires the following underlined feature
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See the comment above in regard to the allowability of claim 82.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER STEPHAN NOGUEROLA whose telephone number is (571)272-1343. The examiner can normally be reached on Monday - Friday 9:00AM-5:30 PM EST.
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, Luan Van can be reached on 571 272-8521. 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.
/ALEXANDER S NOGUEROLA/ Primary Examiner, Art Unit 1795
1 Although not relied upon for this claim rejection the Examiner suggests that Applicant take note of the numerous Hel308 sequences disclosed in WO 2013/057495 A2, such as listed in Table 4, which is on pages 23-34.
2 The specification can be used as a dictionary to learn the meaning of a term in the claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999)("[W]ords in patent claims are given their ordinary meaning in the usage of the field of the invention, unless the text of the patent makes clear that a word was used with a special meaning."); Renishaw PLC v. Marposs Societa' per Azioni, 158 F.3d 1243, 1250, 48 USPQ2d 1117, 1122 (Fed. Cir. 1998) ("Where there are several common meanings for a claim term, the patent disclosure serves to point away from the improper meanings and toward the proper meanings."). "The Patent and Trademark Office (‘PTO’) determines the scope of the claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction ‘in light of the specification as it would be interpreted by one of ordinary skill in the art.’ " Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) (en banc) (quoting In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364, 70 USPQ2d 1827, 1830 (Fed. Cir. 2004); see also MPEP § 2111.01. Further, those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application). In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970). The court in Vogel recognized "that it is most difficult, if not meaningless, to try to say what is or is not an obvious variation of a claim," but that one can judge whether or not the invention claimed in an application is an obvious variation of an embodiment disclosed in the patent or application which provides support for the claim. According to the court, one must first "determine how much of the patent disclosure pertains to the invention claimed in the patent" because only "[t]his portion of the specification supports the patent claims and may be considered." The court pointed out that "this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined." In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010); Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003).
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See MPEP 804 II.B.2(a).