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 .
Election/Restrictions
Applicant’s election without traverse of the species of the nucleotide sequences encoding secretion signal peptides of SEQ IDNO: 86 and 89 from species A; the nucleotide sequence encoding the linker sequence of SEQ ID NO: 15 from species B; the promoter sequence of SEQ ID NO: 26 from species C; the termination sequence of SEQ ID NO: 19 from species D; and the therapeutic antibody of Trastuzumab from species E, in the reply filed on 05/07/2029 is acknowledged. However, SEQ ID NO: 86 and 89 are not listed in the claims. For the interest of compact prosecution, nucleotide sequences encoding the first and second secretion peptides selected from SEQ ID NO: 1-4 and 85 will be examined. Therefore, the election of species requirement from the sequences encoding the secretion signal peptides of SEQ ID NO: 1-4 and 85 has been withdrawn.
Claims 1-15, drawn to a polynucleotide vector comprising: nucleotide sequences encoding a light chain and heavy chain antibody of Trastuzumab, preceded at its V terminal end by a first and second heterologous secretion signal peptide of SEQ ID NO: 1-4 and 85; said light and heavy chain being separated by a nucleotide sequence encoding the self-cleavage linker of SEQ ID NO: 15; the promoter of SEQ ID NO: 26 operably linked with the nucleotide sequences encoding said light and heavy chains in the microalgae Phaeodactylum tricornnutum ; the translation termination sequence of SEQ ID NO: 19, and optionally, at least one detectable marker; are examined in this office action.
The nucleotide sequences encoding linker sequences of SEQ ID NO: 6-9, 12 and 16-17; the promoter sequences of SEQ ID NO: 27-37; the terminator sequences of SEQ ID NO: 20-22, 63 and X ; and the therapeutic antibody of rituximab, trastuzumab adalimumab, bevacizumab, infliximab, cetuximab, motavizumab, palivizumab alemtuzumab, dinutuximab, naxitamab, but also comprising for instance, benralizumab, catumaxomab, daratumumab, elotuzumab, epratuzumab, farletuzumab, galiximab gemtuzumab ozogamicin, ibritumomab tiuxetan, lumiliximab, necitumumab, nimotuzumab ocrelizumab, ofatumumab, oregovomab, pertuzumab, tositumomab, zalutumumab, and zanolimumab, more preferably Rituximab, dinutuximab and naxitamab, are withdrawn from consideration as being directed to the non-elected species.
Claim Rejections - 35 USC § 112
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.
Claims 3-15 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.
Claims 3-4, 6, 11 and 15 are indefinite in the recitation of the terms “preferably”, “for instance”, “more preferably” because it is unclear if the limitations after the terms are intended to be part of the alternative or if the claims are limited to the preference. Dependent claims 5, 7-10 and 12-14.
Claim 3 is indefinite because what is encompassed by “L1” and “H7” is unknown and because claim 1 does not recite L1 and H7 signal peptides . it is suggested that claim 3 be amended to replace “claim 1” with ---claim 2---.
Claim 4 is indefinite because claim 1 does not recite the signal peptides B of SEQ ID NO: 85 and E of SEQ ID NO: 1. it is suggested that claim 4 be amended to replace “claim 1” with ---claim 2---.
Clarification is required to more clearly define the metes and bounds of the claims.
Written Description Rejection
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.
Claims 1-15 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.
The claims are broadly drawn to a polynucleotide vector comprising: nucleotide sequences encoding a light chain of therapeutic monoclonal antibody, fragment or derivative thereof, and heavy chain antibody, fragment or derivative thereof , preceded at its V terminal end by a first and second heterologous secretion signal peptide; said light and heavy chain being separated by a nucleotide sequence encoding the self-cleavage linker; the promoter is operably linked with the nucleotide sequences encoding said light and heavy chains for expression in the microalgae Phaeodactylum tricornnutum ; a translation termination sequence, and optionally, at least one detectable marker. Dependent claims 2-4 and limit the heterologous signal peptides to SEQ ID NO: 1-4 and 85; dependent claims 6 and 10 limit the linker peptide to SEQ ID NO: 15; dependent claims 7 and 9 limit the promoter to SEQ ID NO: 26; dependent claims 8 and 10 limit the terminator sequence to SEQ ID NO: 19; and dependent claim 15 limits the therapeutic antibody to Trastuzumab.
According to the specification, the heterologous signal peptide sequences of SEQ ID NO: 1-4 and 85, the promoter sequence of SEQ ID NO: 26, and the anticancer mAb of Trastuzumab are known in the prior art. The “antibody fragment”, “functional fragment”, and “derivatives” of the claims are broadly defined on pages 23-24 of the specification. However, the structure and the identity of “ fragment”, “functional fragment”, and “derivative” of the therapeutic monoclonal antibody of Trastuzumab are unknown.
The Federal Circuit has recently clarified the application of the written description requirement to inventions in the field of biotechnology. See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398; 1406 (Fed. Cir. 1997). In summary, the court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. The court goes on to say, “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNAs, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559; 43 USPQ2d 1398, 1406 (Fed. Cir. 1997).
The specification fails to describe a representative species of the genus of nucleotide sequences encoding the light chain and heavy chain of therapeutic monoclonal antibody, fragment or derivative thereof, including functional fragments and derivates of the therapeutic monoclonal antibody of Trastuzumab; the genus of sequences encoding secretion signal peptides; and the genus of operable promoter and termination sequences. Neither the specification nor the prior art provides structure-function correlation of the nucleotide sequences encoding the light chain and heavy chain of the therapeutic antibody . Substantial variations in structure and function are expected among fragments and derivatives of the light chain and heavy chain of therapeutic monoclonal antibody.
The specification only describes unmodified nucleic acid sequences of SEQ ID NO: 2-3 and 6 and methods of transforming maize plants with said nucleic acid sequences for enhanced resistance to gray leaf diseases. Furthermore, the specification fails to describe structural features common to members of the claimed genus of nucleic acid sequences. Therefore, the specification has not met either of the two elements of the written description requirement as set forth in the court's decision in Eli Lilly, and has not shown her/his possession of the claimed genus at the time of the application. Since the specification fails to adequacy describe the nucleic acid sequences as broadly claimed, expression cassettes, recombinant vectors or microorganism comprising said nucleic acid sequences, and methods that employ with said nucleic acid sequences are similarly not described.
Therefore, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that Applicant was in possession of the invention as broadly claimed at the time of filing.
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 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over each of Franziska Hempel (Microbial Cell Factories (2012) 11(1): 126; Applicant’s IDS) and Vanier et al (PLOS One (2015) 10(10) page e0139282; Applicant’s IDS) in view of Collins et al (WO 2017/129723; Applicant’s IDS) and Applicant’s admitted prior art (
The claims are drawn to a single polynucleotide vector expressing a therapeutic monoclonal antibody or a functional fragment or derivative thereof, said vector sequence comprising: nucleotide sequences encoding, in the same or in two different Open Reading Frame(s): the light chain of said therapeutic antibody, fragment or derivative thereof, preceded at its V-terminal end by a first heterologous secretion signal peptide, the heavy chain of said therapeutic antibody, fragment or derivative thereof,
preceded at its /V-terminal end by a second heterologous secretion signal peptide, said light and heavy chain being separated by a nucleotide sequence encoding a self-cleaving linker, at least one promoter operatively linked with the sequences encoding said light and heavy chains, said promoter being able to drive the expression of said light and heavy chains in the microalgae Phaeodactylum tricornutum; at least one translation termination sequence, and optionally, at least one detectable marker; wherein said heterologous secretion signal peptide is selected from SEQ ID NO: 1-4 or 85, wherein said first and second heterologous secretion signal peptides are identical or different; wherein said first and second heterologous secretion signal peptides are followed by a sequence encoding a cleavage site, wherein said linker is
SEQ ID NO: 15 and said promoter is SEQ ID NO: 26, and the termination sequence is SEQ ID NO: 19. The claims are also drawn to a transformed cell of Phaeodactylum tricornutum comprising the polynucleotide vector of claim 1, said cell is from the strain Ptl, Pt3, Pt4, Pt5 or Pt7; a method of using the transformed cell of claim 11, comprising
producing and secreting a therapeutic antibody, a functional fragment or derivative thereof.; and an invitro method for producing a therapeutic antibody, a functional
fragment or derivative thereof, said method comprising culturing the transformed cell in appropriate culture conditions; harvesting the extracellular medium of said culture, and
purifying the therapeutic antibody, fragment or derivative thereof, which is secreted in
said extracellular medium; said culture conditions comprising a culture medium containing a nitrate concentration comprised between 0, g/L and 1g/L and low salt concentration comprised between 5 to 30%; wherein said therapeutic
antibody is a chimeric, humanized, or human anti-viral, auto-immune or anticancer antibody or any variant from Trastuzumab or derivatives.
Franziska Hempel et al (2017) teach a vector comprising nucleotide sequences encoding the light chain and the heavy chain of an antibody including sequences encoding signal sequences, and a method of expressing said light and heavy chains in the microalgae Phaeodactylum tricornutum under the control of the nitrate reductase promoter and terminator sequences of the P. tricornutum; and transformed P. tricornutum cells. The antibody was expressed by the algae and secreted into salt water culture medium ; a purified functional antibody was isolated from the culture medium (Fig. 1b). At page 4, Hempel et al (2017) cite their previous work discovery that showed the human IgG antibody efficiently expressed from the nuclear genome with production levels of ~ 9% of the total soluble protein (Hempel (2011)) and that the antibody can also be secreted into the culture medium (Hempel et al (2012)). At page 5, column 1, Franziska Hempel et al state “[e]specially humanized antibodies are of course interesting for potential therapeutic applications”. Vanier et al (2015), cited in Franziska Hempel et, teach production of human anti-hepatitis B monoclonal antibody in the microalgae P. tricornutum and focused on the characterization of its C- and N-terminal extremities, its signal peptide cleavage site and post-translational modifications . Vanier et la describes that the expression of the light and heavy chains of an antibody from two promoters in a single vector results in secretion of glycosylated antibody and also describe the role of signal peptides in targeting and translocation of secreted proteins.
Each of Franziska Hempel et al and Vanier et al do not teach a sequence encoding self-cleavage linker, and sequences encoding heterologous signal peptide of SEQ ID NO: 1-4 and 85 in the vector.
Collin et al teach a multigene expression system comprising at least two nucleotide sequences connected to one another by at least one sequence encoding a linker peptide, and expression of several proteins from a single open reading frame under the control of at least one promoter, wherein each protein is separated by the self-cleaving viral 2A peptides that allow for efficient multigene expression in P. tricornutum cells (pages 1-2; Example 1); the cell culture medium containing salt concentration of between 5 to 30% in the culture medium and nitrate concentration between 0,1 and 1g/L of claim 15 is obvious over the culture medium of the prior art. .
Each of Franziska Hempel et al and Vanier et al in view of Collin et al do teach the secretion signal sequences of SEQ ID NO: 1-4 and 85. However, Applicant’s admitted prior art references on page 7 of the specification showing that the signal peptides of SEQ ID NO: 1-4 and 85 are known and have been used in the prior art for secretion.
Therefore, it would have been obvious to one or skill in the art before the effective filing date of the claimed invention to obtain a vector comprising nucleotide sequences with signal sequences encoding the light chain and the heavy chain of an antibody signal peptides, and a method of expressing said light and heavy chains in the microalgae Phaeodactylum tricornutum under the control of the nitrate reductase promoter and terminator sequences of the P. tricornutum as taught by each of Franziska Hempel et al and Vanier et al, and to modify that vector by including a sequence encoding the self-cleaving peptide linker of 2A taught by Collins, given that the 2A peptide allows efficient multigene expression in P. tricornutum cells as taught by Collins et al. One would have been motivated to include the signal peptide sequences of SEQ ID NO: 1-4 and 85 for targeted secretion, given that the sequences are well described and available, and given that secretion of antibody into the culture medium is taught by Vanier et al. The specification does not show unexpected results obtained with the use of cells from Pt1, Pt3, Pt4, Pt5 or Pt7 strains, therefore claim 11 is included in the rejection.
Therefore, from the teachings of the references, it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 6-10 and 15 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the linker sequences of SEQ ID NO: 6-9, 12, and 15-17 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: each linker sequence is structurally and functionally different from the other promoter sequences, and are from different sources. Likewise, the Markush grouping of the promoter sequences of SEQ ID NO: 26-37 or the termination sequences of SEQ ID NO: 19-22, 63 and X is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: each promoter sequence is structurally and functionally different from the other promoter sequences, and are from different sources. The therapeutic antibodies of claim 15 do not share both a single structural similarity and a common use for the following reasons: each antibody is structurally and functionally different from each other and are from different sources.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Conclusion
No claim is allowed.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MEDINA AHMED IBRAHIM whose telephone number is (571)272-0797. The examiner can normally be reached Monday-Friday, 9:00 - 6:00.
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MEDINA AHMED. IBRAHIM
Primary Examiner
Art Unit 1662
/MEDINA A IBRAHIM/ Primary Examiner, Art Unit 1662
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