DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of Claims
Currently, claims 7 and 17-29 are pending in the instant application. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied or are reiterated. They constitute the complete set being presently applied to the instant Application. This action is Non-FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Improper Markush Group
Claims 7 and 17, 19-21, 23-24, and 26-28 are rejected under the judicially approved “improper Markush grouping” doctrine. (See Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, page 7166). This rejection is appropriate when claims contain an improper grouping of alternatively useable species. See In re Harnisch, 631 F. 2d 716, 719-20 (CCPA 1980).
The claims are directed to a kit that comprises oligonucleotides comprising probes that target at least ten different chromosomal regions set forth in the claimed table. Therefore, the claims are directed to alternative combinations of oligonucleotides. A Markush claim contains an ‘improper Markush grouping’ if : (1) the species of the Markush group do not share a ‘single structural similarity,’ or (2) the species do not share a common use.
MPEP 803.02 provides guidance on the analysis of a proper Markush group. The MPEP sets forth:
Since the decisions in In re Weber, 580 F.2d 455, 198 USPQ 328 (CCPA 1978) and In re Haas, 580 F.2d 461, 198 USPQ 334 (CCPA 1978), it is improper for the Office to refuse to examine that which applicants regard as their invention, unless the subject matter in a claim lacks unity of invention. In re Harnisch, 631 F.2d 716, 206 USPQ 300 (CCPA 1980); and Ex parte Hozumi, 3 USPQ2d 1059 (Bd. Pat. App. & Int. 1984). Broadly, unity of invention exists where compounds included within a Markush group (1) share a common utility, and (2) share a substantial structural feature essential to that utility.
In the instant situation, the specification teaches identification of circulating nucleic acid biomarkers that were found in prostate cancer subjects. Regions within human chromosomes that comprise these circulating nucleic acids are set forth in the table in claim 7. However, each of the chromosome regions are from different human chromosomes, each anywhere from tens of thousands to hundreds of thousands of kilobases long. The claims are directed to oligonucleotides with a sequence that “target” and “selectively hybridize” to these sections. However, the instantly claimed, generally recited oligonucleotides do not share any common structural element that is essential to the asserted utility of being associated with prostate cancer. Although the oligonucleotides all contain sequences that are found within the human genome, they are composed of different sequences in different chromosomes and distinct genetic contexts. None of these regions are structurally the same, nor do they encode transcripts that are the same. The only structural similarity present is that the claimed oligonucleotides contain nucleotides. However, the fact that the regions and oligonucleotides comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with prostate cancer. Thus when considering the different oligonucleotides that fall within the regions in the tables, recited in the alternative, there does not appear to be any common structure related to the function of the oligonucleotides in the claims.
Additionally, the MPEP at 2117 IIA states that a recognized physical, chemical, or an art recognized class is a class where there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. It is specifically stated that “Thus a Markush grouping is ordinarily proper if all the members for the group belong to a recognized class (whether physical, chemical, or art recognized) and are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed invention, and it is clear from their very nature or from the prior art that all members possess this property (emphasis added)”. This applies when "there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention." However the specification has not shown evidence establishing an expectation in the art that the members of the claimed class, encompassing a wide range circulating nucleic acid molecules having disparate chemical and physical properties, will behave the same way in the context of the claimed invention. See MPEP § 2117(IV)(D) ("the members of the Markush grouping do not share a substantial structural feature" where "defining component (b) represent a plurality of chemical classes with varying structures"). Additionally, neither the specification nor the art has established that the members share a structural feature that is essential to their common use as biomarkers for prostate cancer. Therefore, it is not clear from their very nature or from the prior art that all members possess the property of functioning as prostate cancer biomarkers.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
Response to Arguments
The response traverses the rejection. The response asserts that the claims are directed to kits comprising oligonucleotides that are FRET hybridization probes, molecular beacon probes, or molecular scorpion probes and as such they have a particular structure that undergo a specific structural change upon hybridization to a target and emit a fluorescent signal. This argument has been thoroughly reviewed but was not found persuasive because the limitation directed to the type of fluorescent probes is not a structural element that is essential to the asserted utility of being associated with prostate cancer. If that were the case, any FRET hybridization probe, molecule beacon probe, or molecular scorpion probe would be associated with prostate cancer, regardless of the oligonucleotide sequence of the probe. However, the oligonucleotide sequence of the probe is essential because that is the region that is target specific. In the instant situation, the structural element which is essential to the asserted utility is each chromosome region, which do not share a structural similarity because although the oligonucleotides all contain sequences that are found within the human genome, they are composed of different sequences in different chromosomes and distinct genetic contexts. None of these regions are structurally the same, nor do they encode transcripts that are the same. Furthermore, the fact that the regions and oligonucleotides comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with prostate cancer. Accordingly, the rejection is maintained.
Claim Rejections - 35 USC § 112
Claims 7 and 17-29 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. 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.
Relevant to the lack of particular structural limitations in the rejected claims drawn to oligonucleotides, MPEP 2163 states:
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.
Additionally, at 2163IIA3(a), the MPEP states:
“…describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene “because it is only an indication of what the gene does, rather than what it is.”); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”).
The claims are directed to “oligonucleotides comprising probes” that target at least 10 different chromosomal regions set forth in the claims. The claim also recites that each probe “selectively” hybridizes to a segment of the chromosomal region it targets. Therefore, the claims encompass an enormous genus of possible oligonucleotide probes that functionally “selectively” hybridize to hundreds of thousands of different nucleotides. At paragraph 0024, the specification defines the term “hybridization” to include duplex formation with less than 100% complementarity between a probe and a target nucleic acid strand. Therefore, the claims also encompass oligonucleotides that are not 100% complementary to the targets they are designed to hybridize to. At paragraph 0025, the specification teaches that “stringent, sequence specific hybridization” conditions under which an oligonucleotide will hybridize only to the target sequence are sequence dependent and will be different under different circumstances. However, the specification does not teach what oligonucleotide sequences will only hybridize to regions set forth in the claims and not to any other nucleic acid target. Accordingly, the skilled artisan would not be able to determine which probes fall within the scope of the claimed genus (those that “target” and “selectively” hybridize) vs those that do not. Additionally, the designation of the chromosomal regions is not fixed. The claims do not provide any context to what position “1” is to be able to determine which nucleotide sequences are encompassed by the regions set forth in the claimed table. Different versions of each chromosome exist in the art, and as the chromosomal sequences are updated, the nucleotide positions can change.
While the skilled artisan may be capable of making probes that hybridize to the claimed positions and test different conditions to determine which do not cross hybridize to other targets, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
For claims drawn to a genus, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. Further, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“ [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Thus considering the breadth of the oligonucleotide probes required by the claimed kits, their specific required functionalities, and the teachings of the instant specification, it is the conclusion that the specification does not provide an adequate written description of the broadly claimed subject matter.
Claims 7 and 17-29 are 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.
The claims are directed to “oligonucleotides comprising probes” that target at least 10 different chromosomal regions set forth in the claims. The claim also recites that each probe “selectively” hybridizes to a segment of the chromosomal region it targets. However, the metes and bounds of the term “selectively hybridizes” is not clear. At paragraph 0024, the specification defines the term “hybridization” to include duplex formation with less than 100% complementarity between a probe and a target nucleic acid strand. At paragraph 0025, the specification teaches that “stringent, sequence specific hybridization” conditions under which an oligonucleotide will hybridize only to the target sequence are sequence dependent and will be different under different circumstances. However, the specification does not teach what oligonucleotide sequences will only hybridize to regions set forth in the claims and not to any other nucleic acid targets. Therefore, the metes and bounds of the claimed oligonucleotides are not clear. Do the oligonucleotides have to be completely complementary to the target they hybridize to or is some variability allowed? What is the structure of oligonucleotides that fall within the scope of the claims vs those that do not? Accordingly, one of ordinary skill in the art would not be apprised of the scope of the claimed kits.
Additionally, the claimed table appears to recite numerical positions within particular chromosomes, however, not only are the columns not defined, but no context is given as to what positions these numbers correspond to. It is not clear what the reference sequence is or what position “1” is. Different versions of each chromosome exist in the art, and as the chromosomal sequences are updated, the nucleotide positions can change. Therefore, the metes and bounds of the claimed regions, and therefore the probes that hybridize to them, is unclear.
Response to Arguments
The response traverses both rejections (35 USC 112(a) and 112(b)) in the same section. The response asserts that the insight provided by the instant specification is that specific biomarkers are associated with prostate cancer and that the data presented in the specification documenting the surprising usefulness of the claimed invention, including the use of commercially available primers and adapters to quantify levels of such biomarkers. The response cites to Example 1 and tables 1-4 and asserts that those of skill in the art reading the specification would be aware of the existence, usefulness, and structural features of the recited fluorescent probes. This argument has been thoroughly reviewed but was not found persuasive because the usefulness of the recited claims has not been called into question. Additionally, neither Example 1 nor tables 1-4 teach the identity or specific oligonucleotide sequence of any fluorescent probes or adapters. The office action has not asserted that one of skill in the art would be incapable of making oligonucleotides that would hybridize to some portion of the chromosome regions set forth in the claims. However, the claims recite that each probe “selectively” hybridizes to a segment of the chromosomal region it targets and the specification teaches at paragraph 0025 that “stringent, sequence specific hybridization” conditions under which an oligonucleotide will hybridize only to the target sequence are sequence dependent and will be different under different circumstances. Therefore, the claimed genus appears to encompass probes that only hybridize to a region set forth in the claims but not to any other nucleic acid target. However, the specification does not teach the sequence of any oligonucleotide which will only hybridize to regions set forth in the claims and not to any other nucleic acid target. Accordingly, the skilled artisan would not be able to determine which probes fall within the scope of the claimed genus (those that “target” and “selectively” hybridize) vs those that do not.
Additionally, the response asserts that the specification teaches the numbered regions are according to the hg18/build 36.1 version of the genome released in March 2006. However, it is noted that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). For these reasons and the reasons already made of record, the rejection is maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 7 and 17-29 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over NEB catalog (1998/1999), pp. 121, 284 in view of Rothstein (Rothstein et al; PNAS, vol 91, Pages 4155-4159; 1994).
The NEB catalog offered for sale a random primer mix of 6, 9, 12 and 24 mer primers. As the calculation below shows, with regard to the 24mers, about 9 molecules of every 24 mer are statistically expected to be present in each tube,
Molecular weight of 24-mer:
24 x 325 daltons/nucleotide = 7,800 daltons = 7,800 g/mol
Total number of possible 24-mers:
424 = 2.8 x 1014 molecules
How many molecules of 24-mer in a vial sold by NEB:
1 A260 unit = 33 mg = 3.3 x 10-5 g
3.3 x 10-5 g / 7,800 g/mol = 4.2 x 10-9 mol
(4.2 x 10-9 mol) x (6.02 x 1023 molecules/mol) = 2.5 x 1015 molecules
d. How many molecules of each 24-mer in a single vial:
2.5 x1015 molecules / 2.8 x 1014 molecules = 9 molecules/vial
The claims encompass a very large genus of possible nucleic acids with no particular base composition or length. The NEB catalog vials will inherently and necessarily contain 24 mer nucleotide primers encompassed by the broadly claimed recitation in claims. The NEB catalog does not teach the primers are fluorescently labeled, however it does teach that they can be so labeled for DNA visualization and cites Rothstein. Rothstein teaches labeling universal primers from NEB with fluorescein conjugated dUTP. Therefore it would have been prima facie obvious to the ordinary artisan at the time the invention was made to label the 24 mers taught by NEB with the method of Rothstein because both NEB and Rothstein teach to do so.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 7 and 19-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 10/214,775 in view of Purwosunu (Purwosunu et al; Methods in Molecular Biology, vol 444: Prenatal Diagnosis, pages 231-238; 2008 Humana Press).
It is noted that the instant application claims priority as a divisional application of application 14/414,882. However, the instantly pending claims were not filed in the parent application and were not subject to any restriction requirement. It is additionally noted that even if the claims had been submitted in the parent application, the entire restriction requirement in the ‘882 parent application was withdrawn in the office action dated 4/6/2018. Accordingly, the mere designation of the instant application as a “divisional” does not bar an obviousness type double patenting rejection over the conflicting patent claims. See MPEP 804.01.
The claims of the ‘775 patent are directed to method of detecting circulating cell free DNA where the sequences of cell free DNA are those that are recited in the instantly pending claims. The claims do not teach using molecular beacon probes, however Purwosunu teaches successful detection of circulating cell free DNA using molecular beacon probes (see whole document). Therefore it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to have constructed molecular beacon probes comprising oligonucleotides that target the instantly claimed chromosome regions with a reasonable expectation of success.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to examiner Jehanne Sitton whose telephone number is (571) 272-0752. The examiner is a hoteling examiner and can normally be reached Mondays-Fridays from 8:00 AM to 2:00 PM Eastern Time Zone.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Winston Shen, can be reached on (571) 272-3157. The fax phone number for organization where this application or proceeding is assigned is (571) 273-8300.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
Prosecution Insights