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 .
Election/Restrictions
Applicant's election without traverse of invention Group I, claims 18-35, and of the signal peptide species ‘SEQ ID NO: 4’, the host cell species ‘Aspergillus niger’, and of the enzyme species ‘amylase’ in the reply filed on 12/16/2025 is acknowledged. Claims 36-37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Claims 31 is withdrawn because the claim is are directed to a non-elected species.
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Claim Status
The amendment of 12/16/2025 has been entered. Claims 18-37 are pending (claim set as filed on 05/02/2023 ). Claims 36-37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claim 31 is withdrawn since it is directed to a non-elected species. Election was made without traverse in the reply filed on 12/16/2025.
Claims 18-30 and 32-35 are currently under examination and were examined on their merits.
Priority
This application filed on 05/02/2023 claims priority to PCT application no. PCT/EP2021/080303, filed on 11/02/2021, and claims foreign priority to application no. DKPA202001235, filed on 11/02/2020. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 05/02/2023 (2 pages) was considered. The information disclosure statement filed on 05/02/2023 (5 pages) was considered in part. This IDS fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. Specifically, the citations of Non-patent literature documents number 1 (“CN - 107475219 - Database accession no. BET72940”), and number 5 (“WO - 1989001969A1 - Database accession no. AAP94634), are missing the publication date and publisher information, and the citation of Non-patent literature document number 2 (“KUSUYA ET AL., 2019, Database accession no. A0A401KWX5”) is missing the publisher information. Therefore, these documents have not been considered.
In order to have the struck-through references in the IDS considered by the Examiner, Applicant is asked to submit a new IDS having listed therein only the struck-through documents from this IDS. The IDS should be accompanied by a copy of each struck-through reference.
Claim Interpretation
Claims 23 and 29 recite the transitional phrase “consists essentially of’. The MPEP states:
“For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355 ("PPG could have defined the scope of the phrase ‘consisting essentially of’ for purposes of its patent by making clear in its specification what it regarded as constituting a material change in the basic and novel characteristics of the invention.").” (See MPEP 2111.03)
The Applicant does not point out in the Specification how the transitional phrase ‘consisting essentially of’ relates to the claimed invention, and does not explain what would be considered a significant material change in the characteristics of the claimed invention. Absent any indication within the instant Disclosure of what the Applicant means by 'consisting essentially of’, the Examiner interprets the phrase ‘consisting essentially of’ as ‘comprising’ for the purpose of this examination.
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 and 25-28 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 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 § 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 18-30 and 32-35 are rejected under 35 U.S.C. 103 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 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 (“[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,” (paragraph 0045]).
Regarding claim 22, pertaining to the leader peptide, Li teaches wherein the leader peptide is heterologous 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,”; paragraph [0044]-[0045]).
Regarding claim 24, pertaining to the polypeptide of interest, Li teaches wherein the polypeptide of interest is secreted (“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, 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 see interpretation of the transitional phrase “consists essentially of” under Claim Interpretation above. Pertaining to the third polynucleotide, Li teaches wherein the third polynucleotide encodes a signal peptide comprises, consists essentially of, 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 Election/Restrictions 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 Election/Restrictions 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, consists essentially of, or consists of SEQ ID NO: 2 (FARAPVAAR) (instant claim 23). Pertaining to claim 23, please note the interpretation of the transitional phrase “consists essentially of” under Claim Interpretation above.
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, consists essentially of, 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.
Conclusion
No claims are allowed.
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
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653