DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
The amendment of 05/28/2026 has been entered. Claims 18-21, 23 and 25-37 are pending (claim set as filed on 05/28/2026). Claims 31, 36-37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election of Invention group I, drawn to an Aspergillus host cell, and election of the signal peptide species ‘SEQ ID NO: 4’, of the host cell species ‘Aspergillus niger’, and of the enzyme species ‘amylase’ was made without traverse in the reply filed on 12/16/2025.
Claims 18-21,23, 25-30, and 32-35 are currently under examination and were examined on their merits.
Claim Rejections - 35 USC § 112(a)
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 18-20, 25-28, 30, 32-35 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as necessitated by amendment, as failing to comply with the written description requirement.
The claim 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.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as
broadly as their terms reasonably allow. Claims 18-20 are directed in part to genera of leader peptides having a sequence identity at least 80%, 90%, and 95% with SEQ ID NO: 2, and claims 25-28 are directed in part to genera of signal peptide having a sequence identity of at least 80%, 90%, 95%, and 98% with SEQ ID NO: 4, wherein the structure of the recited variants is not further specified.
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for
the Federal Circuit has held that “A written description of an invention involving a chemical
genus, like a description of a chemical species, ‘requires a precise definition, such as by
structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it
from other materials”. As indicated in MPEP § 2163, the written description requirement for a
claimed genus may be satisfied through sufficient description of a representative number of
species by actual reduction to practice, reduction to drawings, or by disclosure of relevant,
identifying characteristics, i.e., structure or other physical and/or chemical properties, by
functional characteristics coupled with a known or disclosed correlation between function and
structure, or by a combination of such identifying characteristics, sufficient to show that
Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that 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.
There is either (a) no structural limitation, or (b) a significant amount of structural variability with respect to the members of the genera of leader peptide variants and of the genera of signal peptide variants required by the claims. While the specification in the instant application discloses the structure of the leader peptide sequence SEQ ID NO: 2 and of the signal peptide sequence SEQ ID NO: 4, it provides no clue as to the structural elements required in any leader peptide and signal peptide, nor does it teach which structural elements within SEQ ID NO: 2 or SEQ ID NO: 4 are required in any leader peptide variant or any signal peptide variant, respectively. Moreover, while the specification describes wherein leader peptides, and leader peptides as part or in combination with different signal peptides, are used for improved expression, activity, and/or yield of a heterologous protein (page 2, lines 9-15), the specification is silent to those structural features in any leader peptide or signal peptide, that are associated with improved expression, activity and/or yield of a heterologous protein. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which variants of the polypeptides of SEQ ID NO: 2 or SEQ ID NO: 4 would have the desired properties to provide improved expression, activity, and/or yield of a heterologous protein.
The claims encompass a large genus of proteins which are structurally unrelated or
substantially unrelated in structure. A polypeptide having 80% sequence identity with the polypeptide of SEQ ID NO: 2 allows for any combination of 1.8 amino acid modifications within SEQ ID NO: 2 (1.8 = 0.2x9; SEQ ID NO: 2 has 9 amino acids). The total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula N!x19A/(N-A)!/A!, where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. Thus, the total number of variants of the polypeptide of SEQ ID NO: 2 having 80% sequence identity to the polypeptide of SEQ ID NO: 2 that result from amino acid substitutions is 9!x191.8/(9-1.8)!/1.8! or 1.44x104 variants. Similar calculations for variants of the polypeptide of SEQ ID NO: 2 having 90% and 95% sequence identity to the polypeptide of SEQ ID NO: 2 yield about 127 and 34 variants, respectively. Regarding SEQ ID NO: 4, calculations for variants of the polypeptide of SEQ ID NO: 4 having 80%, 90%, 95%, and 98% sequence identity to the polypeptide of SEQ ID NO: 4 result in about 2.39x1010, 1.93x106, 9.25x103, and 72 variants, respectively (SEQ ID NO: 4 has 21 amino acids). A sufficient written description of a genus of polypeptides may be achieved by a recitation of a representative number of polypeptides defined by their amino acid sequence or a recitation of structural features common to members of the genus. However, in the instant case, there are no specific variants derived from SEQ ID NO: 2 or SEQ ID NO: 4 described in the instant application, or the recited structural feature, for example, 80% sequence identity to SEQ ID NO: 2 or SEQ ID NO: 4, is not representative of all the members of the genus of leader peptides or signal peptides recited since there is no information as to which are the structural elements within the polypeptide of SEQ ID NO: 2 or SEQ ID NO: 4 that are essential for the recited function, which are the remaining structural elements required in the recited polypeptides in addition to those recited in the claims such that the desired improved expression, activity, and/or yield of a heterologous protein is displayed, or a correlation between structure and function which would provide those unknown structural features. It is further noted that the art teaches how even highly structurally homologous peptides can have different functional properties. For example, Allison et al. (“Mutations in the Signal Sequence of Prepro-a-Factor Inhibit Both Translocation into the Endoplasmic Reticulum and Processing by Signal Peptidase in Yeast Cells”, published in 1989, Molecular and Cell Biology, Vol. 9, No. 11, pages 4977-4985), teaches wherein single amino acid substitutions within the signal sequence of yeast prepro-α-factor resulted in the accumulation of mostly unglycosylated prepro-α-factor, indicating a defect in translocation of the protein into the endoplasmic reticulum (see entire document, including abstract), thereby emphasizing the need of either recitation of a representative number of polypeptides defined by their amino acid sequence, or of recitation of structural features common to members of the genus.
Due to the fact that the specification discloses no variant species derived from the leader peptide SEQ ID NO: 2 and no variant species derived from signal peptide SEQ ID NO: 4 required by the claims, and the lack of description of variant species by any relevant, identifying structural characteristics or properties that are required for the desired function of the peptides for improved expression, activity, and/or yield of a heterologous protein, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Claim Rejections - 35 USC § 112 (b)
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 18-21, 23, 25-30, and 32-35 are newly rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as necessitated by amendment, 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.
Claim 18 recites the method steps “wherein the leader peptide is cleaved off the polypeptide of interest, leaving a mature polypeptide of interest, wherein the mature polypeptide of interest is secreted” (lines 13-15) which renders the claim indefinite since it is unclear how the method steps of cleaving and secreting are related to the composition Aspergillus cell comprising in its genome polynucleotides operably linked in translational fusion. One of ordinary skill in the art would not be able to determine the metes and bounds of claim 18, and therefore, could not clearly determine how to avoid infringement of the claim.
In the interest of compact prosecution, the recited “wherein the leader peptide is cleaved off from the polypeptide of interest, leaving a mature polypeptide of interest, and wherein the mature polypeptide of interest is secreted” is treated as a property of the polynucleotides operably linked in translational fusion (see description of “translational fusion” in the specification, page 9, lines 25-25), i.e. if the operably linked polynucleotides are translated, the leader peptide can be cleaved off the polypeptide of interest to leave a mature polypeptide of interest, wherein the mature polypeptide of interest is secreted.
Claims 19-21, 23, 25-30, and 32-35 are further rejected since they do not clarify the indefinite language of claim 18.
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.
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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 18-21, 23, 25-30 and 32-35 are newly rejected under 35 U.S.C. 103 as necessitated by amendment as being unpatentable over Li et al. (US 2013/0031676 A1, published on 01/31/2013), hereinafter ‘Li’, in view of Nielsen et al. (US 2003/0027290 A1, published on 02/06/2003), hereinafter ‘Nielsen’.
Li’s general disclosure relates to “isolated polypeptides having glucoamylase activity and isolated polynucleotides encoding the polypeptides” (see entire document, including abstract).
Regarding claims 18-21, 23, 25-30, and 32-35, please note the 112b rejection above.
Regarding claim 18, pertaining to the Aspergillus host cell, Li teaches an Aspergillus host cell (“fungal host cell is an Aspergillus niger cell”; paragraph [0147]) comprising in its genome (“The vectors of the present invention preferably contain an element(s) that permits integration of the vector into the host cell's genome”; paragraphs [0123], [0126]):
a first polynucleotide encoding a polypeptide of interest (“The present invention relates to isolated polypeptides having glucoamylase activity and isolated polynucleotides encoding the polypeptides. The invention also relates to nucleic acid constructs, vectors, and host cells comprising the polynucleotides”; paragraph [0004]); and
a second polynucleotide operably linked in translational fusion to the first polynucleotide upstream of the first polynucleotide, said second polynucleotide encoding a leader peptide (“The control sequence may also be a propeptide coding sequence that encodes a propeptide positioned at the amino terminus of a polypeptide.”; paragraphs [0044]-[0046], [0117]). Li describes that a propeptide is cleaved off from the polypeptide of interest in order to convert the polypeptide of interest into the mature active polypeptide (paragraph [0117]). It is noted that the instant specification describes that “the leader peptide is cleaved off the polypeptide of interest, leaving a mature polypeptide of interest” (page 7, lines 4-5). As such, Li’s term ‘propeptide’ reads on the instant term ‘leader peptide’.
Li teaches wherein the host cell comprises in its genome a third polynucleotide encoding a signal peptide (“The control sequence may also be a signal peptide coding sequence that encodes a signal peptide linked to the amino terminus of a polypeptide”, “; paragraphs [0044]-[0046], [0113], [0116], [0121], [0123], [0126]),
wherein the third polynucleotide is operably linked in translational fusion to the second polynucleotide (“[w]here both signal peptide and propeptide sequences are present at the amino terminus of a polypeptide, the propeptide sequence is positioned next to the amino terminus of a polypeptide and the signal peptide sequence is positioned next to the amino terminus of the propeptide sequence” (paragraph [0118]), and
wherein the leader peptide is heterologous to the signal peptide and to the polypeptide of interest (“control sequences required for expression of a coding sequence”; “[e]ach control sequence may be native or foreign to the nucleotide sequence encoding the polypeptide or native or foreign to each other. Such control sequences include, but are not limited to, a leader, polyadenylation sequence, propeptide sequence, promoter, signal peptide sequence,” (paragraphs [0044]-[0045]).
As discussed above under Claim Rejections - 35 USC § 112 (b), the Examiner interprets “wherein the leader peptide is cleaved off the polypeptide of interest, leaving a mature polypeptide of interest, and wherein the mature polypeptide of interest is secreted” recited in instant claim 18 as a property of the recited translational fusion.
Li further teaches wherein the leader peptide is cleaved off the polypeptide of interest, leaving a mature polypeptide of interest (“A propeptide is generally inactive and can be converted to a mature active polypeptide by catalytic or autocatalytic cleavage of the propeptide from the propolypeptide”; paragraph [0117]), and wherein the mature polypeptide of interest is secreted (“a signal peptide linked to the amino terminus of a polypeptide and directs the encoded polypeptide into the cell's secretory pathway”; paragraphs [0080], [0113]).
Regarding claims 25-28, please note the election of the signal peptide species ‘SEQ ID NO: 4’ under Claim Status above. Pertaining to the third polynucleotide, Li teaches wherein the third polynucleotide encodes a signal peptide that has 100% sequence identity with instant SEQ ID NO: 4 (instant claims 25-28) (“In a preferred aspect, the signal peptide comprises or consists of amino acids 1 to 21 of SEQ ID NO: 2”; paragraph [0116]; please see the alignment of instant SEQ ID NO: 4 with amino acids 1-21 of Li’s SEQ ID NO: 2 below).
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Regarding claim 29, please note the election of the signal peptide species ‘SEQ ID NO: 4’ under Claim Status above. Pertaining to the third polynucleotide, Li teaches wherein the third polynucleotide encodes a signal peptide comprises or consists of instant SEQ ID NO: 4 (“the signal peptide comprises or consists of amino acids 1 to 21 of SEQ ID NO: 2”; paragraph [0116]; please see sequence alignment of instant SEQ ID NO: 4 with amino acid 1-21 of Li’s SEQ ID NO: 2 above).
Regarding claims 30 and 32, please note Applicant’s election of the Aspergillus host cell species ‘Aspergillus niger’ under Claim Status above. Pertaining to the Aspergillus host cell, Li teaches wherein the Aspergillus host cell is an Aspergillus niger cell (“In another most preferred aspect, the filamentous fungal host cell is an Aspergillus niger cell”; paragraph [0147]).
Regarding claim 33, pertaining to the polypeptide of interest, Li teaches wherein the polypeptide of interest is an enzyme (“The present invention relates to isolated polypeptides having glucoamylase activity and isolated polynucleotides encoding the polypeptides”, “Glucoamylase (…) is an enzyme”; paragraph [0006], [0017]; see abstract).
Regarding claim 34, please note Applicant’s election of the enzyme species ‘amylase’ under Claim Status above. Pertaining to the enzyme, Li teaches wherein the enzyme is an amylase (“The present invention relates to isolated polypeptides having glucoamylase activity and isolated polynucleotides encoding the polypeptides.”, “Glucoamylase (…) is an enzyme”; paragraph [0006], [0017]; see abstract).
Regarding claim 35, pertaining to the enzyme, Li teaches wherein the enzyme is a glucoamylase (“The present invention relates to isolated polypeptides having glucoamylase activity and isolated polynucleotides encoding the polypeptides.”, “Glucoamylase (…) is an enzyme”; paragraph [0006], [0017]; see abstract).
In addition, Li discloses that “ the term "control sequences" is defined herein to include all components necessary for the expression of a polynucleotide encoding a polypeptide of the
present invention”, and that “control sequences include, but are not limited to, a leader, polyadenylation sequence, propeptide sequence, promoter, signal peptide sequence, and transcription terminator” (paragraph [0045]; see claim 49).
Li does not teach wherein the leader peptide has a sequence identity of at least 80% to SEQ ID NO: 2 (FARAPVAAR) (instant claim 18), wherein the leader peptide has a sequence identity of at least 90% to SEQ ID NO: 2 (FARAPVAAR) (instant claim 19), wherein the leader peptide has a sequence identity of at least 95% to SEQ ID NO: 2 (FARAPVAAR) (instant claim 20), wherein the leader peptide (propeptide) has a sequence identity of at least 98% to SEQ ID NO: 2 (FARAPVAAR) (instant claim 21), and wherein the leader peptide comprises or consists of SEQ ID NO: 2 (FARAPVAAR) (instant claim 23).
Nielsen’s general disclosure relates to an isolated thermostable glucoamylase
derived from Talaromyces emersonii (see entire document, including abstract).
Regarding claim 18, pertaining to a host cell, Nielsen teaches
a first polynucleotide encoding a polypeptide of interest (“thermostable glucoamylase from a strain of Talaromyces emersonii“, “The terms "glucoamylase" and "AMG" are used interchangeably”; paragraphs [0011], [0013], [0035], [0199]; see amino acids 28-618 in Fig. 5A-5B and in SEQ ID NO: 34; see claim 15); and
a second polynucleotide operably linked in translational fusion to the first polynucleotide upstream of the first polynucleotide, said second polynucleotide encoding a leader peptide having a sequence identity of 100% to instant SEQ ID NO: 2 (FARAPVAAR) (see amino acids 19-27 (FARAPVAAR) in Fig. 5A and SEQ ID NO: 34),
wherein a third polynucleotide is operably linked in translational fusion to the second polynucleotide upstream of the second polynucleotide (paragraphs [0035] and [0199]); see encoded sequence MASLVAGALCILGLTPAA corresponding to amino acids 1-18 in Fig. 5A and SEQ ID NO: 34).
Nielsen teaches wherein the sequence comprising the third and second polynucleotide together encode the polypeptide sequence ‘MASLVAGALCILGLTPAAFARAPVAAR’ (see amino acids 1-27 in Fig. 5A and SEQ ID NO: 34), wherein ‘MASLVAGALCILGLTPAAFA’ is considered a putative signal peptide and ‘RAPVAAR’ is considered a putative propeptide (“Putative signal and pro-peptides are double underlined and dotted underline, respectively”; paragraph [0035], see Fig. 5A). It is noted that the instant specification discloses that “[in a preferred embodiment, the propeptide is a leader peptide with SEQ ID NO: 2” (page 26, lines 30-31).
While Li does not teach a leader peptide having a sequence identity of at least 80% to SEQ ID NO: 2 (FARAPVAAR)(instant claim 18), it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have combined Li’s teachings with Nielsen’s teachings on the putative propeptide from Talaromyces emersonii, to have created an Aspergillus host cell comprising a second polynucleotide encoding a leader peptide (RAPVAAR) having a sequence identity of about 77% to SEQ ID NO: 2 (FARAPVAAR)(please see alignment below). One would have been motivated to do so to improve the expression of the polypeptide of interest, since Li teaches that control sequences, including propeptides, direct the expression of a polypeptide in an expression host (paragraph [0045], see claim 49).
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While modified Li does not teach wherein the leader peptide has a sequence identity of at least 80%, at least 90%, at least 95%, and at least 98% sequence identity to SEQ ID NO: 2 (FARAPVAAR) (instant claims 18-21), and wherein the leader peptide comprises or consists of the SEQ ID NO: 2 (instant claim 23), the recited leader peptide ‘FARAPVAAR’ would have been within the realm of routine experimentation, since Nielsen teaches the putative nature of the signal peptide ‘MASLVAGALCILGLTPAAFA’ and of the propeptide ‘RAPVAAR’, which are comprised by the polypeptide ‘MASLVAGALCILGLTPAAFARAPVAAR’ (see amino acids 1-27 in Fig. 5A and SEQ ID NO: 34; paragraphs [0035 ]and [0199]). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have manipulated the length of Nielsen’s propeptide by extending the N-terminus of the propeptide ‘RAPVAAR’ with one or several C-terminal amino acids of the putative signal peptide sequence, including the last two C-terminal amino acid residues F and A from the putative signal peptide ‘MASLVAGALCILGLTPAAFA’, since the exact length of Nielsen’s propeptide is unknown (paragraph [0035]), and thus to have arrived at the claimed leader peptide ‘FARAPVAAR’ SEQ ID NO: 2). One would have been motivated to do so, for the benefit of further improving production of Li’s polypeptide of interest (see Li, paragraph [0045], see claim 49).
A skilled artisan would have reasonably expected success in combining Li’s and Nielsen’s teachings, since both references are directed to polynucleotides encoding signal peptides, propeptides, and glucoamylases as polypeptides of interest.
Response to Arguments
Applicant has traversed the previous rejections of claims 18-20 and 25-28 under 35 U.S.C. 112(a) and of claims 18-30 and 32-35 under 35 U.S.C. 103 in the remarks filed on 05/28/2026 (remarks, pages 5-8). Applicant's arguments have been fully considered but they are not persuasive.
Applicant states that “claim 18 is amended and narrowed to include the limitations of both previously pending claims 22 and 24”, that “[n]either of these claims was subjected to the instant rejection”, and that “[f]or at least this reason, the Applicant respectfully requests reconsideration and withdrawal of the rejection under 35 U.S.C. §112” (remarks, page 5).
The Examiner responds that amended claim 18 contains new claim language further narrowing the claim (claim 18, lines 13-15), and as such, claim 18 is newly rejected under 35 U.S.C. 112(a) as necessitated by amendment.
Applicant states that neither Li nor Nielsen, alone or in combination, teaches or suggests the claimed invention (remarks page 7), and further describes that regarding Nielsen’s teachings “there is no suggestion to excise, modify (e.g., by adding "FA" to reach "FARAPVAAR"), or deploy it as a heterologous tool for protein engineering in Aspergillus hosts” (remarks page 7).
The Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Li provides an Aspergillus host cell comprising in its genome a first polynucleotide encoding a polypeptide of interest, a second polynucleotide operably linked in translational fusion to the first polynucleotide upstream of the first polynucleotide, said second polynucleotide encoding a leader peptide, and a third polynucleotide encoding a signal peptide wherein the third polynucleotide is operably linked in translational fusion to the second polynucleotide;and
wherein the leader peptide is heterologous to the signal peptide and to the polypeptide of interest, further wherein the leader peptide can be cleaved off the polypeptide of interest, leaving a mature polypeptide of interest, and wherein the mature polypeptide of interest is secreted. Nielsen provides a polynucleotide encoding the sequence “MASLVAGALCILGLTPAAFARAPVAAR” comprising claimed SEQ ID NO: 2 (“FARAPVAAR”) which is operably linked to an amylase, and wherein “RAPVAAR” is considered a putative propeptide (leader peptide), and MASLVAGALCILGLTPAAFA is considered a putative signal peptide, as discussed above. It would have been obvious to a skilled artisan to have combined Li’s and Nielsen’s teachings to create an Aspergillus cell wherein “RAPVAAR” is used as a leader sequence to improve polypeptide expression since both references are directed to glucoamylase expression. It would have been further obvious to manipulate the length of the leader sequence for enhanced expression based on Nielsen’s teachings on the putative nature of the propeptide.
In response to Applicant's arguments against the references individually (remarks, page 7), the Examiner recognizes that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant describes that “the specific synthetic leader peptide SEQ ID NO: 2 (JPO001), when used in translational fusion upstream of the mature POI and downstream of a heterologous signal improves expression levels, transformation efficiency, and retention of high yield in thermostable variants” (remarks, page 7), and that “[the] results are not suggested or predictable from the generic teachings of Li or the native context of Nielsen” (remarks , page 8).
In response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., improved expression levels, transformation efficiency, and retention of high yield in thermostable variants) are not recited in the rejected claim(s). 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). The Examiner further notes that Applicant’s experimental results are considered a property of the claimed composition. Since Li in view of Nielsen teaches the claimed composition, experiments performed with modified Li’s composition would have the same or similar results. Applicant’s results are not considered unexpected since Li teaches the use of a leader sequence to direct the expression of a polypeptide of interest (paragraphs [0045]-[0046], [0099], [0117]-[0118], [0121]).
Applicant states that “[t]he combination is hindsight-driven. See In re Deuel, 51 F.3d 1552, 1559 (Fed. Cir. 1995)” (remarks, page 8).
In response to Applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
No claims are allowed.
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.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SANDRA ZINGARELLI whose telephone number is (703)756-1799. The examiner can normally be reached M-F 9-5.
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/SANDRA ZINGARELLI/ Examiner, Art Unit 1653
/JENNIFER M.H. TICHY/Primary Examiner, Art Unit 1653
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