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 .
DETAILED ACTION
Claims 127, 129, 130, 133, 136-139, 142, 146, 147, 153, 156, 159, 160, 164, 166, and 167 are pending and under examination.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9 has been entered.
Response to Arguments
Applicant’s arguments with respect to the rejection of claims 127, 129, 130, 133, 136-139, 142, 146, 147, 153, 156, 159, 160, 164, 166, and 167 under 35 USC 103, have been considered but are not persuasive. Applicant has amended independent claim 127 to recite: wherein the template polynucleotide sequence is a cDNA fragment sequence that is 45-450 nucleotides long. Applicant argues that Humphrey-Smith and Hammond do not teach said cDNA fragment. However, Humphrey-Smith teaches that the array is useful for the purpose of determining the protein profile of a biological sample, and that the array may be used to ascertain any subset of an organism’s proteome, such as the protein profile of a particular cell, tissue, or organ either in a healthy or diseased state (Page 50, Paragraph 2). Humphrey-Smith teaches that preferred synthetic peptides for use in constructing the array will comprise at least 5 to 80 amino acids in length (Page 26, Paragraph 1). Humphrey-Smith teaches that the recombinant peptides of the invention will be derived from isolated nucleic acid molecules, including cDNA sequences (Page 29, Paragraph 4). A cDNA sequence encoding a peptide that is 5 to 80 amino acids in length would be approximately 15-250 nucleotides long, which includes lengths recited in the instant claim. Therefore, it would have been obvious to one of ordinary skill in the art that the array of Humphrey-Smith may be in the form of a peptide library, that the peptides sequences may be encoded by cDNA sequences of 15-250 nucleotides, and that the peptides in said library may be derived from diseased cells.
Applicant also argues that Humphrey-Smith does not teach a frame-check sequence and a need for one does not exist because one of ordinary skill would have understood that the nucleic acid encoding the protein would be in the correct reading frame. However, said statement is merely an allegation and there is no evidence presented in Humphrey-Smith to suggest that a frame-check sequence would be unnecessary. As stated, Humphrey-Smith explicitly teaches the addition of one or more reporter molecules which are bound thereto to facilitate detection of said proteins, while Hammond teaches an RNA-affinity tag fusion containing an out-of-frame stop codon, so that if translation were to occur out of frame, the affinity tag would not be translated (i.e., termination of translation) (Page 5, Paragraph 0059).
Therefore, Applicant’s arguments are not considered persuasive.
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.
Claims 127, 129, 130, 133, 136-139, 142, 146, 147, 153, 156, 159, 160, 164, 166, and 167 are rejected under 35 U.S.C. §103 as being unpatentable over Humphrey-Smith et al. (WO 99/39210; previously cited) as evidenced by Snapp 2005 (Design and Use of Fluorescent Fusion Proteins in Cell Biology, previously cited), in view of Hammond et al. (U.S. Pub. No. 2002/0160377 A1, previously cited).
Regarding claim 127, Humphrey-Smith teaches a protein array in which the proteins for the inclusion in the primary array may be produced in the form of a recombinant peptide library, and that “peptide library” shall be taken to mean the inducible protein products of any set of diverse nucleotide sequences encoding a set of diverse amino acid sequences (Page 32, line 19-24). Humphrey-Smith teaches that “protein” includes a fusion protein (Page 20, line 6). Therefore, it is considered that the protein array of Humphrey-Smith may be a peptide library, and that the array/library may contain peptide fusions. Given the broadest reasonable interpretation, “plurality” is interpreted as meaning “more than one”.
Humphrey-Smith teaches that the array comprises redundant proteins that emulate the antigenic diversity of the proteome, which is accomplished via the use of one or more protein expression libraries (Page 19, line 2). Humphrey-Smith teaches that recombinant peptide production can be accomplished by any technique known to those of ordinary skill in the art, and only requires that the nucleotide sequence of the nucleic acid molecule encoding the peptide is presented in expressible format, wherein “expressible format” shall be taken to indicate that a protein-encoding region of a nucleic acid molecule is place in operable connection with a promoter or other regulatory sequence capable of regulating expression in a cellular or cell-free system (Page 29, Paragraph 5). Therefore, it is considered that a start codon is required for “expressible format”, as it is well-known to those of ordinary skill in the art that a start codon is required for proper protein expression. Humphrey-Smith teaches that, generally, promoters are positioned upstream of the genes they control (Page 31, Paragraph 2).
Humphrey-Smith teaches that a “peptide library” further includes cells, virus particles, and bacteriophage particles (Page 33, lines 4-5).
Humphrey-Smith teaches that the array is useful for the purpose of determining the protein profile of a biological sample, and that the array may be used to ascertain any subset of an organism’s proteome, such as the protein profile of a particular cell, tissue, or organ either in a healthy or diseased state (Page 50, Paragraph 2). Humphrey-Smith teaches that preferred synthetic peptides for use in constructing the array will comprise at least 5 to 80 amino acids in length (Page 26, Paragraph 1). Humphrey-Smith teaches that the recombinant peptides of the invention will be derived from isolated nucleic acid molecules, including cDNA sequences (Page 29, Paragraph 4). A cDNA sequence encoding a peptide that is 5 to 80 amino acids in length would be approximately 15-250 nucleotides long, which includes lengths recited in the instant claim. Therefore, it would have been obvious to one of ordinary skill in the art that the array of Humphrey-Smith may be in the form of a peptide library, that the peptides sequences may be encoded by cDNA sequences of 15-250 nucleotides, and that the peptides in said library may be derived from diseased cells.
Humphrey-Smith teaches that the proteins of the array may be modified by the addition of one or more amino acids to their amino or carboxy termini (Paragraph spanning pages 19 and 20), or that they may be modified by the addition of one or more reporter molecules which are bound thereto to facilitate detection of said proteins (i.e., interpreted to be synonymous with affinity tag) (Page 20, lines 14-16). Therefore, it is considered that the array of Humphrey-Smith may be in the form of a peptide library and said peptides may be modified by the addition of an affinity tag.
Humphrey-Smith teaches that the reporter molecule may be produced as an in-frame fusion with the recombinant protein of the array (i.e., the protein of interest) (Page 49, Paragraph 1). Therefore, it is considered that an in-frame reporter sequence linked to the C-terminus of a peptide of interest would constitute a downstream frame-check sequence comprising an affinity tag.
Humphrey-Smith does not teach a frame check sequence that operates to terminate translation of the fusion polypeptide when the template polynucleotide sequence is out of frame with the sequence encoding the affinity tag.
However, Hammond teaches an RNA-affinity tag fusion containing an out-of-frame stop codon, so that if translation were to occur out of frame, the affinity tag would not be translated (i.e., termination of translation) (Page 5, Paragraph 0059).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have added a frame check sequence upstream of the affinity tag, as taught by Hammond, to the fusion protein of Humphrey-Smith. One of ordinary skill in the art would have been motivated to do so because Hammond teaches that including an out-of-frame stop codon allows for selection of only fusions with in-frame stop codons after purification (i.e., only fusions that are correctly in-frame are tagged with the affinity marker/reporter) (Page 5, Paragraph 0059). One of ordinary skill in the art would have a reasonable expectation of success because Humphrey-Smith and Hammond are in the same field of endeavor of recombinant protein development.
Regarding claim 129, although Hammond does not disclose the exact formula presented in instant claim 129, Hammond does teach a sequence comprising at least two stop codons and at least 3 non-stop codons (SEQ IN NO:5). SEQ ID NO:5 contains no stop codons in two of the three potential reading frames (Paragraph 0071), but does contain stop codons in one of the reading frames. It would have been obvious to one of ordinary skill in the art that the stop and non-stop codons could be arranged in any order, including the order presented in the formula of instant claim 129, as stop and non-stop codon sequences are well-known to those of ordinary skill in the art, said artisan recognizing that the position of the stop codons would affect the final recombinant protein being purified.
Regarding claim 130, as stated above, Humphrey-Smith teaches that the reporter molecule may be added to the C-terminus of the protein of the array (Paragraph spanning pages 19 and 20), and teaches that the nucleic acid molecule placed in operable connection with a promoter comprises a nucleic acid sequence encoding the protein of interest (i.e., the protein to be included in the primary array), in addition to one or more nucleotide sequences encoding inteins and/or highly immunogenic peptides (Paragraph spanning pages 29 and 30), wherein intein refers to an excisable protein element or any number of protein purification/enrichment tags linked to a cleavage site for recovery of all or part of a fusion protein from an affinity column (Page 30, line 4). Therefore, it is considered that the affinity tag is linked via a cleavage site to the polynucleotide encoding the protein of interest.
Regarding claim 133, Humphrey-Smith teaches that the reporter that may be added to the protein of the array may be a His-tag (Page 21, Paragraph 4). It is interpreted that, because of the use of the word “or” in instant claim 133, that the affinity tag only requires 1 of (a), (b), or (c).
Regarding claim 136, Humphrey-Smith teaches that the reporter molecules may be functional enzymes, such as green fluorescent protein (Page 21, Paragraph 4), which is an enzyme that would enhance the size of a polypeptide in which it was linked to, as evidenced by, Snapp 2005, which teaches that GFP is approximately 27 kDa (Page 4, Paragraph 4).
Regarding claim 137, as stated above, Humphrey-Smith teaches that a reporter molecule could be added to the C-terminus of the protein, i.e., downstream (Paragraph spanning pages 19 and 20). Therefore, if GFP was added to the C-terminus of a protein in the library it would increase the size of said protein.
Regarding claim 138, although Humphrey-Smith does not explicitly mention that the epitope of a size-enhancing protein may be added, Humphrey-Smith does teach that reporter molecules may be detected by the use of an antibody molecule that binds to said reporter (Page 49, Paragraph 1). It would have been obvious to one of ordinary skill in the art that if an antibody was to be used for detection, the epitope of the reporter must be included in the reporter sequence, as it is well-known that the portion of an antigen that binds the antibody is considered the epitope.
Regarding claim 139, Humphrey-Smith teaches that the proteins of the array may be modified by the addition of one or more reporter molecules which are bound to said protein to facilitate detection (Page 21, lines 14-16), and also teaches that any number of protein purification or enrichment tags linked to a cleavage site for recovery of all or part of a fusion protein from an affinity column may be added (Page 30, lines 4-5). As stated above, Humphrey-Smith teaches the incorporation of reporters that are size enhancing. Therefore, it would have been obvious to one of ordinary skill that at least 2 size enhancing reporters may be linked to each protein in the array.
Regarding claim 142, Humphrey-Smith teaches that GFP be used as a reporter molecule, which is approximately 27 kDa, as evidenced by Snapp 2005, which is over 15 kDa.
Regarding claim 146, Humphrey-Smith teaches that the array is useful for the purpose of determining the protein profile of a biological sample, and that the array may be used to ascertain any subset of an organism’s proteome, such as the protein profile of a particular cell, tissue, or organ either in a healthy or diseased state (Page 50, Paragraph 2). Humphrey-Smith teaches that the invention may be used to compare healthy and diseased tissues from humans (Paragraph spanning pages 53 and 54).
Regarding claim 147, Humphrey-Smith teaches that the invention provides a significant contribution to the characterization of multigenic traits and other multiprotein phenomena that are associated with disease, such as the major diseases of humans (e.g., cancer or autoimmune diseases) (Paragraph spanning pages 53 and 54).
Regarding claim 153, Humphrey-Smith teaches that the recombinant peptides of the invention will be derived from isolated nucleic acid molecules, including PCR products, cDNA sequences, or genomic DNA (Page 29, Paragraph 4).
Regarding claim 156, Humphrey-Smith teaches that the high-density array of the invention comprises a primary and secondary array, in which the secondary array provides unique tags to each of the elements contained within a primary high-density array of proteins (Page 4, Paragraph 3). Humphrey-Smith teaches that for a small bacterial proteome comprising about 4,000 antigens (i.e., proteins in the primary array), up to 12-20 mice will be required to produce a sufficient number of antibodies against complex protein mixtures to represent at least one epitope per protein, for 25-75% of the total proteome (Paragraph spanning pages 41 and 42). Therefore, it is interpreted that the primary array taught by Humphrey-Smith contains sequences that encode at least 25-75% of peptide sequences of the proteome.
Regarding claim 159, as stated, Humphrey-Smith teaches that the array may be used to ascertain any subset of an organism’s proteome, such as the protein profile of a particular cell, tissue, or organ either in a healthy or diseased state (Page 50, Paragraph 2)
Regarding claim 160, Humphrey-Smith teaches that the proteins of the array may be modified by the addition of one or more reporter molecules which are bound to said protein to facilitate detection (Page 21, lines 14-16), but does not explicitly disclose the percentage of proteins that comprise an affinity tag. However, from the disclosure of Humphrey-Smith, one of ordinary skill in the art would be reasonably expected to understand that any of the total proteins expressed in the array may be linked to an affinity tag, said artisan recognizing that the presence of the affinity tag would affect protein purification.
Regarding claim 164, Humphrey-Smith teaches that the number of proteins comprising the protein array will depend on the antigenic diversity of the source cell, tissue, organ, or organism to which the proteome relates. Humphrey-Smith teaches that in the case of a bacterium there may be approximately 4,000 to 20,000 gene products, while in the case of the human proteome, there may be approximately 100,000 to 300,000 gene products (i.e., proteins) (Page 18, Paragraph 3)
Regarding claims 166, Humphrey-Smith teaches that, in the case of the human proteome, there may be approximately 100,000 to 300,000 gene products (i.e., proteins) (Page 18, Paragraph 3) and that the array may be used to ascertain the proteome profile of a cell in a healthy or diseased state (Page 50, Paragraph 2), such as the major diseases of humans (e.g., cancer or autoimmune diseases) (Paragraph spanning pages 53 and 54). Therefore, if the proteome of a cancer cell was analyzed in the array taught by Humphrey-Smith, the cancer cell proteome would inherently contain at least 10-1000 polynucleotides encoding a mutant peptide sequence.
Regarding claim 167, Humphrey-Smith teaches that the array is useful for the purpose of determining the protein profile of a biological sample, and that the array may be used to ascertain any subset of an organism’s proteome, such as the protein profile of a particular cell, tissue, or organ either in a healthy or diseased state (Page 50, Paragraph 2). Humphrey-Smith teaches that the invention provides a significant contribution to the characterization of multigenic traits and other multiprotein phenomena that are associated with disease, such as the major diseases of humans (e.g., cancer or autoimmune diseases) (Paragraph spanning pages 53 and 54).
Therefore, it would have been obvious to one of ordinary skill in the art that the proteome of a cancer cell may be analyzed using the invention of Humphrey-Smith. If the proteome of a cancer cell was analyzed in the array taught by Humphrey-Smith, the cancer cell proteome would inherently contain cancer-cell specific mutant peptide sequences.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL EMILY MARTIN whose telephone number is (703)756-1416. The examiner can normally be reached M-Th 8:30-16:00, F 8:30-10:00 EST.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/RACHEL EMILY MARTIN/Examiner, Art Unit 1657