DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 112
2. 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.
3. Claims 1-2, 6, 8-10, 12, 14-15, 17-18, 22-23, 26, 28-29, 37-39 and 40 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.
Claim 1 is drawn to a library of nucleic acids each encoding for peptides having a length of 25-110 amino acids from a naturally occurring protein of one or more organism. The amino acids encode for 10,000 different peptides of naturally occurring proteins, wherein 50 of the peptides are of a different naturally occurring protein. The specification discloses peptides that are encoded by the library of nucleic acids as fragments of naturally occurring proteins. The claims also include peptides encoded by the nucleic acids, and methods of using the library.
There is no guidance in the specification as to any structural feature that identifies a particular peptide fragment as being from a “naturally occurring” protein. Therefore, of the entire possible genus of encoded protein fragments there is no written description as to which ones are naturally occurring and which ones are not. The specification does not disclose a definition for fragments of naturally occurring protein. The specification discloses a species of nucleic acids that encode for a peptide, but does not disclose other members of the genus. The specification does not describe other members of the genus by any other structural properties, and/or chemical features. The specification does not describe a method to tell which nucleic acids encode for naturally occurring proteins or non-naturally occurring proteins. The specification discloses a method to clone nucleic acid library into expression vectors to screen for phenotype. The specification does not describe how the expression vector changes the function of the species. One of skill in the art would conclude that the applicant would have been in possession of the genus based on the specification and the general knowledge in the art concerning genetic code. The description given is not adequate to allow one of skill in the art to distinguish members of the claimed subgenus from other members of the genus of claim 1. One of skill in the art would conclude that applicant was not in possession of the claimed genus because a description of only one member of this genus is not representative of the species in the genus and is insufficient to support the claim.
The specification fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph, with respect to the full scope of claim 1.
Claim Rejections - 35 USC § 112
4. 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.
5. Claims 1-2, 6, 8-10, 12, 14-15, 17-18, 22-23, 26, 28-29, 37-39 and 40 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.
A. In claim 1, regarding the phrase “wherein each nucleic acid does not contain one or more of GGATCC, CTCGAG, GGGGGG, AAAAAA, TTTTTT, CCCCCC, a hairpin sequence, an in-frame STOP codon except at a terminus of the nucleic acid, or a Kozak sequence except at a start of the nucleic acid,” it is unclear whether the applicants intend for this to mean that each nucleic acid does not contain one or more of the listed limitations (i.e., no nucleic acid has GGATCC, or CTCGAG… or any combination of the listed limitations) or whether they intend for this to mean that each nucleic acid does not contain one or more of EACH limitation from this list (i.e., no nucleic acid contains one or more GGATCC, and does not contain one or more CTCGAG… etc.). Therefore the claim is indefinite. For the purpose of prosecution this claim is being interpreted as the former, that is that each nucleic acid does not contain one or more of the listed limitations.
B. In claim 12, the amended language is unclear in the recitation of the phrase “…encodes for different peptides of at least 1% of the naturally occurring proteins…” Is this limitation intended to suggest that the peptides represent 1% of all naturally occurring proteins (since the naturally occurring proteins are “of one or more organisms” in claim 1) or is it intended that the peptides represent at least 1% of the sequence of each protein represented in the library (i.e., a 1,000 amino acid protein must by represented by at least 10 amino acids “worth” of peptides)? Additionally, regarding the amended phrase “each different peptide differs from its respective naturally occurring protein by one or more amino acids” it is unclear how peptides “selected from the amino acid sequences of naturally occurring proteins” can differ from those naturally occurring proteins by one or more amino acids. These amendments are unclear and therefore the claim is indefinite.
C. In claim 18, regarding the amended phrase “each different peptide differs from its respective naturally occurring protein by one or more amino acids” it is unclear how peptides “selected from the amino acid sequences of naturally occurring proteins” can differ from those naturally occurring proteins by one or more amino acids. Therefore claim 18 is indefinite.
D. In claim 23, it is unclear what it means for a three dimensional structure to be “known”- what entity must “know” the structure to be within the metes and bounds of the claim?
E. In claim 40, it is unclear how the library is expressed in a eukaryotic cell “by cloning into an expression vector.” Therefore the claim is indefinite. For the purpose of prosecution this is being interpreted as though the library was cloned into an expression vector and then expressed in eukaryotic cells.
F. All other claims not discussed here are rejected because the depend from or specifically refer to a previously rejected claim.
Claim Rejections - 35 USC § 101
6. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
7. Claims 1, 2, 6, 8-10, 12, 14, 15, 17, 18, 22, and 23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to nucleic acid library encoding for a peptide having an amino acid sequence of a naturally occurring protein (natural products) without significantly more.
Claim 1 and those that depend from claim 1 are drawn to a product comprising nucleic acids that encode peptides.
The invention falls within a statutory category of invention, namely a composition of matter.
The claimed invention is then analyzed to determine whether it is directed to any judicial exception. The claim requires only nucleic acids encoding amino acid for a peptide of naturally occur protein. The claim requires a library of nucleic acids encoding for a peptide having a length of 25-110 amino acids. The claim requires nucleic acids encoding portions of naturally occurring proteins which are natural products and must be compared to its closest counterpart. A nucleic acid isolated and placed in mixture (i.e., “a library”) is not markedly different from the natural products, i.e., Funk Bros. Thus, the claimed nucleic acid library does not display markedly different characteristics compared to the naturally occurring nucleic acid molecule counterparts. Likewise, the peptide library of claim 27 claims only fragments of naturally occurring peptides that have not shown to be markedly different characteristics from its counterpart of full length molecules.
Accordingly, Claims 1, 2, 6, 8-10, 12, 14, 15, 17, 18, 22, 23, and 27 recite the same judicial exceptions that are nucleic acids of naturally occurring proteins are drawn to a judicial exception (product of nature).
Next, the claim is analyzed for additional elements that integrate the judicial exception into a practical application and then if there are additional elements that amount to significantly more. The claim does not integrate the use of the product of nature, because they are isolated nucleic acids encoding for peptides and no elements in addition to the judicial exception are present. Furthermore, the dependent claims do not add any structural feature that distinguishes nucleic acid molecules and sets of nucleic acid molecules from their full length counterparts. The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The claim(s) do not qualify as eligible subject matter and are drawn to judicial exceptions.
Claim Rejections - 35 USC § 102
8. 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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.
9. Claims 1-2, 6, 8-10, 12, 14-15, 17-18, 22-23, 26, 28-29, 37-39 and 40 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Hardwick et al (International Patent Application No. WO 2017109499 A1, published 2017-06-29).
Regarding claim 1, Hardwick teaches a library of DNA coding sequences (i.e., a library of nucleic acids each comprising a coding region) encoding for short expressed peptides (SEPs) having a length of 40 to 60 amino acids ([pg. 3 ¶ 6]), that these SEPs are in silico designed to only use expressed proteins from a proteome consensus database (i.e., are regions of a sequence selected from an amino acid sequence of a naturally occurring protein [pg. 4 ¶ 3]), and that these SEPs come from a single species or from mixed origins (i.e., one or more organisms [pg. 4 ¶ 2]).
Hardwick also teaches that this library comprises 1x106 different amino acid or nucleic acid sequences (i.e., at least 10,000 different such peptides). Hardwick teaches that the expressed proteins are from a proteome consensus database, and that the library is “spaced across all proteins in the human proteome and is present in a complete inventory” ([pg. 4 ¶ 3]). The limitation of “at least 50 of such peptides is a sequence region of the amino acid sequence of a different protein of a plurality of different such naturally occurring proteins” is inherently taught by a library that covers the entirety of the human proteome.
Additionally, Hardwick teaches that a human SEP library is designed to be in frame with no premature STOPs due to frameshifts ([pg. 4, ¶ 3]), therefore each nucleic acid of the library does not contain an in-frame STOP codon except at a terminus of the nucleic acid. Hardwick teaches that fragments are generated by massively parallel synthesis (i.e., synthetic [pg. 4 ¶ 3]).
Regarding claims 2, 6 and 8, Hardwick teaches that the expressed proteins are from a proteome consensus database, and that the library is “spaced across all proteins in the human proteome and is present in a complete inventory” ([pg. 4 ¶ 3]). The limitation of “at least 50 of such peptides is a sequence region of the amino acid sequence of a different protein of a plurality of different such naturally occurring proteins” wherein the different such naturally occurring proteins are at least 50 of either: proteins associated with cancer, a cytoplasmic protein, proteins that bind to a given protein or at least one protein from a functional class of proteins, is a cytoplasmic kinase, or a protein that binds to KRas, is inherently taught by a library that covers the entirety of the human proteome.
Regarding claims 9 and 10, Hardwick teaches that an SEP library that comprises 1x106 different amino acid or nucleic acid sequences (i.e., at least 10,000 or 50,000 different such peptides). Hardwick teaches that the expressed proteins are from a proteome consensus database, and that the library is “spaced across all proteins in the human proteome and is present in a complete inventory” ([pg. 4 ¶ 3]). The limitation of “at least 100 or 1,000 of such peptides is a sequence region of the amino acid sequence of a different protein of a plurality of different such naturally occurring proteins” is inherently taught by a library that covers the entirety of the human proteome.
Regarding claim 12, Hardwick teaches an SEP library comprising peptides “spaced across all proteins in the human proteome and is present in a complete inventory” ([pg. 4 ¶ 3]), and that these peptides are expressed as fusions with other heterologous peptides (i.e., each peptide differs from its respective naturally occurring protein by at least one or more amino acids [pg. 12 ¶ 7]).
Regarding claims 14 and 15, Hardwick teaches an SEP library comprising peptides “spaced across all proteins in the human proteome and is present in a complete inventory” ([pg. 4 ¶ 3]). Since the language of this claim only requires that the peptide library comprises different peptides sequence from non-consecutive sequence regions, the library taught by Hardwick teaches this limitation as a library covering the entire human proteome comprises peptides having non-consecutive sequence regions along the naturally occurring protein. Additionally, Hardwick teaches that peptides are 40-60 (i.e., about 55) amino acids long ([pg. 3 ¶ 6]), therefore each non-consecutive amino acid sequence is inherently spaced 1 – about 55 amino acids apart.
Regarding claim 17, Hardwick teaches a library of 1x106 different peptides ([pg. 12 ¶ 2]).
Regarding claim 18, Hardwick teaches an SEP library comprising peptides “spaced across all proteins in the human proteome and is present in a complete inventory” ([pg. 4 ¶ 3]). This library inherently comprises a mean number of “greater than 1” nucleic acids per naturally occurring protein since Hardwick teaches that the peptides are 40-60 amino acids long and the average protein in the human proteome is larger than 80-120 amino acids (i.e., would be represented by two peptides encoded by at least two nucleic acids). Hardwick teaches that these peptides are expressed as fusions with other heterologous peptides (i.e., each peptide differs from its respective naturally occurring protein by at least one or more amino acids [pg. 12 ¶ 7]).
Regarding claim 22, Hardwick teaches a library designed from a proteome consensus database (i.e., a reference proteome [pg. 4 ¶ 3]).
Regarding claim 23, Hardwick teaches a library that is rationally selected from fragments of larger proteins based on predictions of domain structures (i.e., naturally occurring proteins with a known three-dimensional structure [pg. 6, ¶ 2]).
Regarding claim 26, Hardwick teaches an SEP library contained in a lentiviral vector ([pg. 22 ¶ 4]).
Regarding claim 28, Hardwick teaches a method of identifying a target protein ([pg. 15 ¶ 3]) comprising: exposing an in vitro population of cultured mammalian cells capable of displaying a phenotype to a library of SEPs, identifying in said cell population an alteration in said phenotype following said exposure, the selection of said cell undergoing the phenotypic change and identifying an SEP that alters the phenotype of the cell, and providing said SEP and identifying the cellular protein that binds to said SEP ([pg. 14, ¶ 3]).
Regarding claim 29, Hardwick teaches an additional step of identifying a test compound which binds to said target protein and displaces or blocks binding of said SEP ([pg. 16 ¶ 2]). Hardwick additionally teaches that compounds are tested for their ability to recapitulate the phenotype of the original SEP (i.e., the compound modulates the phenotype of the cell [pg. 18 ¶ 7]).
Regarding claim 37, Hardwick teaches assays configured to assess the effect of an SEP on various K-Ras-activated signaling pathways ([pg. 15 ¶ 2]).
Regarding claim 38, Hardwick teaches the expression of affinity-tagged SEPs (i.e., identified peptides) used in pull-down assays to isolated and identify protein targets by mass spectrometry ([pg. 15 ¶ 3]). Hardwick additionally teaches the identification of surface sites that participate in signal transduction ([pg. 16 ¶ 6]).
Regarding claim 39, Hardwick teaches SEPs that differentially effect diseased cells versus normal cells ([pg. 15 ¶ 2]), and that diseased cells are cancer cells ([pg. 16 ¶ 5]). If a cancer cell is “differentially effected” then the cell-signaling pathway is inherently active.
Regarding claim 40, Hardwick teaches a method of making a library of peptides. Hardwick teaches designing a library according to claim 1 as discussed fully above and incorporated here, and Hardwick teaches that the library is expressed in KMB7 cells (i.e., a human cell line) after transduction by a lentiviral vector ([pg. 22 ¶ 3]). If the library of peptides are contained in a lentiviral vector, then they were inherently “cloned into an expression vector.”
Response to Arguments
10. Any issue not repeated in the Office Action was overcome by amendment to the claims.
With regard to the previous rejection under 35 U.S.C. 112(a), applicant amended claim 1 to additionally recite “wherein each nucleic acid does not contain one or more of GGATCC, CTCGAG, GGGGGG, AAAAAA, TTTTTT, CCCCCC, a hairpin sequence, an in-frame STOP codon except at a terminus of the nucleic acid, or a Kozak sequence except at a start of the nucleic acid.” Applicant provides no additional remarks as to how this amendment is intended to overcome the rejection.
This argument is not found persuasive because this amendment only describes what characteristics that the members of the nucleic acid library do not have, it does not further describe any structural features that the library does have that identifies any encoded peptide fragment as being from a “naturally occurring” protein. Therefore, this rejection is maintained.
With regard to the previous rejection under 35 U.S.C. 101, applicant argues on page 9 of their remarks that details offered in the specification provided structural features of the claimed library that do not correspond to isolated nucleotides found in nature.
This argument is not found persuasive, as the features described in the specification are not specifically claimed and therefore not required limitations of the claimed nucleic acid library. Neither independent claim 1 nor any of its dependent claims provide any structural feature that distinguishes nucleic acid molecules and sets of nucleic acid molecules in claim 1 from their full length counterparts found in nature. Therefore, this rejection is maintained.
Regarding claims 1, 2, 6, 8-10, 12, 14, 15, 17, 18, 22, 23, 26-29, and 37-39, Applicant argues that neither Hardwick nor Baynes teach the additional limitation recited in the amendment of claim 1. However, as discussed previously in this Office Action, Hardwick teaches an oligonucleotide library that is designed to be in-frame with no premature STOPs due to frameshifts ([pg. 4 ¶ 3]). This teaching overcomes the limitation as claimed, providing a library wherein “each nucleic acid does not contain… an in-frame STOP codon except at a terminus of the nucleic acid.”
11. 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.
Conclusion
12. No claims are allowed.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIAN ELLIS YOUNG whose telephone number is (703)756-5397. The examiner can normally be reached M-F 0730 - 1700.
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/BRIAN ELLIS YOUNG/Examiner, Art Unit 1684
/JULIET C SWITZER/Primary Examiner, Art Unit 1682