DETAILED ACTION
Status of the Application
Claims 1, 3-20, 22-23 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A preliminary amendment cancelling claims 2 and 21 as submitted in a communication filed on 6/24/2026 is acknowledged.
Applicant’s election with traverse of Group I, claims 1-6 and 15, directed in part to a dairy protein that has a substitution of a potentially phosphorylated amino acid with a negatively charged amino acid, as submitted in a communication filed on 6/24/2026 is acknowledged.
Applicant’s traverse is on the grounds that claim 1 has been amended to now require the potentially phosphorylated amino acid to be selected from serine and threonine, and that Goyal et al. do not teach or suggest the technical feature as now claimed. Applicant’s arguments have been fully considered but not deemed persuasive to withdraw the restriction requirement. As set forth in the prior Office action, the restriction requirement is based on the claims as presented at the time the restriction requirement was issued. It is reiterated herein that the technical feature linking Groups I-VI is a dairy protein that comprises a substitution of a potentially phosphorylated amino acid with a negatively charged amino acid, which is shown by Goyal et al. to lack novelty or inventive step because Goyal et al. teach a variant of the bovine casein of SEQ ID NO: 1 of the instant application that comprises an aspartic acid at a position corresponding to position 47 of the polypeptide of SEQ ID NO: 1, wherein an aspartic acid has been replaced with a glutamic acid. Aspartic acid is a potentially phosphorylated amino acid as evidenced by Hardman et al. In addition, even if it is assumed that the technical feature linking all the inventions is that of claim 1 as currently recited, as indicated below, Jebb et al. teach a variant of the bovine casein of SEQ ID NO: 1 of the instant application that comprises a substitution of a serine to an aspartate at the position corresponding to position 15 of the polypeptide of SEQ ID NO: 1. See alignment in Claim Rejections under 35 USC § 101. Thus, the technical feature does not make a contribution over the prior art and the claimed inventions do not meet the requirement of unity of invention under PCT Rule 13.2. The requirement is deemed proper and therefore is made FINAL.
Claims 7-14, 16-20, 22-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 6/24/2026.
Claims 1-6 and 15 are at issue and will be examined to the extent they encompass the elected invention.
Specification
The specification is objected for not complying with sequence rules. While Figure 1 displays an amino acid sequence, neither the drawings nor the Brief Description of the Drawings indicate the corresponding sequence identifier. Applicant is required to insert the corresponding sequence identifier in the Brief Description of the Drawings or amend the drawings to include the sequence identifier in front of the sequence. See particularly 37 CFR 1.821(d). Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See page 17, line 27; page 19, line 7; page 23, line 9; page 33, line 27; page 34, lines 25-26; page 45, lines 24-25; page 46, lines 2 and 6. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code. See MPEP § 608.01.
Priority
Acknowledgment is made of a claim for foreign priority under 35 U.S.C. 119(a)-(d) to AUSTRALIA 2021904275 filed on 12/24/2021. Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
This is the US national application which entered the national stage from PCT/IB2022/062639 filed on 12/21/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/7/2024 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings submitted on 6/21/2024 have been reviewed and are accepted by the Examiner for examination purposes.
Claim Objections
Claim 15 is objected to due to its dependency on a nonelected invention. Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3-6, 15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to products of nature without significantly more. The claims recite a polypeptide which is a variant of a dairy protein, wherein said variant comprises an aspartic acid or a glutamate at a position corresponding to a position in the dairy protein that comprises a serine or a threonine. The specification discloses the polypeptide of SEQ ID NO: 1 as a bovine A2 β-casein (dairy protein). Therefore, the claims encompass a
protein which is a variant of the polypeptide of SEQ ID NO: 1, wherein said protein comprises an aspartic acid or a glutamate at a position corresponding to a position in the polypeptide of SEQ ID NO: 1 that comprises a serine or a threonine. It should be noted that the protein of claims 1, 3-6, 15 is not limited with regard to additional mutations with respect to the polypeptide of SEQ ID NO: 1. All that is required is that the protein claimed has the recited substitutions. See Claim Rejections under 35 USC § 112(b) or Second Paragraph (pre-AIA ) below for claim interpretation. Thus, a protein that comprises the recited substitutions as well as additional modifications is also encompassed by the claims. This judicial exception is not integrated into a practical application because claims 1, 3-6, 15 are directed to a naturally occurring protein as evidenced by Jebb et al. (GenBank accession number KAF6499636, 8/7/2020). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because claims 1, 3-6, 15 fully encompass a naturally-occurring protein. As shown in the alignment below, Jebb et al. disclose a Molossus molossus β-casein that is a variant of the polypeptide of SEQ ID NO: 1 that comprises a substitution of a serine to an aspartate at the position corresponding to position 15 of the polypeptide of SEQ ID NO: 1. See underlined/bold/italicized residue. Please note that in the absence of any additional distinguishing feature not naturally found in a protein, the term “a modified diary protein” is a product-by-process limitation which does not convey any structural and/or functional differences between a man-made and a naturally-occurring product. Also, for the reasons extensively discussed below under Claim Rejections under 35 USC § 112(b) or Second Paragraph (pre-AIA ), claim 6 has been interpreted as a duplicate of claim 1. As such, the claims encompass subject matter which is not patent-eligible.
SEQ ID NO:1
RESULT 264
A0A7J8JS28_MOLMO
ID A0A7J8JS28_MOLMO Unreviewed; 460 AA.
AC A0A7J8JS28;
DT 07-APR-2021, integrated into UniProtKB/TrEMBL.
DT 07-APR-2021, sequence version 1.
DT 08-OCT-2025, entry version 15.
DE RecName: Full=Beta-casein {ECO:0000256|ARBA:ARBA00018977};
GN ORFNames=HJG59_003409 {ECO:0000313|EMBL:KAF6499636.1};
OS Molossus molossus (Pallas' mastiff bat) (Vespertilio molossus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Chiroptera; Yangochiroptera; Molossidae;
OC Molossus.
OX NCBI_TaxID=27622 {ECO:0000313|EMBL:KAF6499636.1, ECO:0000313|Proteomes:UP000550707};
RN [1] {ECO:0000313|EMBL:KAF6499636.1, ECO:0000313|Proteomes:UP000550707}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=MMolMol1 {ECO:0000313|EMBL:KAF6499636.1};
RC TISSUE=Muscle {ECO:0000313|EMBL:KAF6499636.1};
RX PubMed=32699395;
RA Jebb D., Huang Z., Pippel M., Hughes G.M., Lavrichenko K., Devanna P.,
RA Winkler S., Jermiin L.S., Skirmuntt E.C., Katzourakis A., Burkitt-Gray L.,
RA Ray D.A., Sullivan K.A.M., Roscito J.G., Kirilenko B.M., Davalos L.M.,
RA Corthals A.P., Power M.L., Jones G., Ransome R.D., Dechmann D.K.N.,
RA Locatelli A.G., Puechmaille S.J., Fedrigo O., Jarvis E.D., Hiller M.,
RA Vernes S.C., Myers E.W., Teeling E.C.;
RT "Six reference-quality genomes reveal evolution of bat adaptations.";
RL Nature 583:578-584(2020).
CC -!- FUNCTION: Important role in determination of the surface properties of
CC the casein micelles. {ECO:0000256|ARBA:ARBA00002287}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000256|ARBA:ARBA00004613}.
CC -!- SIMILARITY: Belongs to the beta-casein family.
CC {ECO:0000256|ARBA:ARBA00008083}.
CC -!- CAUTION: The sequence shown here is derived from an EMBL/GenBank/DDBJ
CC whole genome shotgun (WGS) entry which is preliminary data.
CC {ECO:0000313|EMBL:KAF6499636.1}.
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DR EMBL; JACASF010000001; KAF6499636.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A7J8JS28; -.
DR InParanoid; A0A7J8JS28; -.
DR Proteomes; UP000550707; Unassembled WGS sequence.
DR GO; GO:0005615; C:extracellular space; IEA:TreeGrafter.
DR InterPro; IPR001588; Casein.
DR InterPro; IPR016345; Casein_beta.
DR InterPro; IPR031305; Casein_CS.
DR PANTHER; PTHR11500; BETA CASEIN; 1.
DR PANTHER; PTHR11500:SF0; BETA-CASEIN; 1.
DR Pfam; PF00363; Casein; 2.
DR PROSITE; PS00306; CASEIN_ALPHA_BETA; 2.
PE 3: Inferred from homology;
KW Milk protein {ECO:0000256|ARBA:ARBA00022743};
KW Phosphoprotein {ECO:0000256|ARBA:ARBA00022553};
KW Reference proteome {ECO:0000313|Proteomes:UP000550707};
KW Secreted {ECO:0000256|ARBA:ARBA00022525};
KW Signal {ECO:0000256|ARBA:ARBA00022729, ECO:0000256|SAM:SignalP}.
FT SIGNAL 1..15
FT /evidence="ECO:0000256|SAM:SignalP"
FT CHAIN 16..460
FT /note="Beta-casein"
FT /evidence="ECO:0000256|SAM:SignalP"
FT /id="PRO_5029807080"
FT REGION 41..74
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 44..62
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 63..72
FT /note="Low complexity"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ SEQUENCE 460 AA; 51488 MW; 49F7C3273A7424A8 CRC64;
Query Match 40.4%; Score 442.5; Length 460;
Best Local Similarity 49.0%;
Matches 102; Conservative 21; Mismatches 82; Indels 3; Gaps 3;
Qy 2 ELEELNVPGEIVESLSSSEESITRINK-KIEKFQSEEQQQTEDELQDKIHPFAQTQSLVY 60
| |:|:: || : ||||| ||| | | |:: :||| ||| | :| | | | |
Db 17 EKEQLSITSVTVEDIEGSEESIMHINKQKPETFENNKQQQKEDERQAQIQPIVQPQPLRP 76
Qy 61 PFPGPIPNS-LPQNIPPLTQTPVVVPPFLQPEVMGVSKVKEAMAPKHKEMPFPKYPVEPF 119
:| || | ||| || | | :| | |||||||| || : |||| || | || |
Db 77 RYPEPISYPVLSQNILPLAQ-PAMVLPVLQPEVMGVPSTKETIFPKHKVMPLLKSPVVPI 135
Qy 120 TESQSLTLTDVENLHLPLPLLQSWMHQPHQPLPPTVMFPPQSVLSLSQSKVLPVPQKAVP 179
: | |||: | ||||:||: | | | | | | ||: ||| || || :
Db 136 VQRQIPNLTDLRNAQLPLPVLQALMSQVPQTLVQTPTLPTQSLFSLSHPNALPFSQKVMT 195
Qy 180 YPQRDMPIQAFLLYQEPVLGPVRGPFPI 207
|| ||:| ||||||:| | | :|:
Db 196 QLQRAMPVQTLLLYQEPLLDPTREFYPV 223
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
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 1, 3-6, 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 pre-AIA the applicant regards as the invention.
Claim 1 (claims 3-6, 15 dependent thereon) is indefinite in the recitation of “…dairy protein in which at least one potentially phosphorylated amino acid selected from serine…and threonine…has been replaced with a negatively charged amino acid” for the following reasons. As known in the art and also admitted in the specification, a protein having the same amino acid sequence can be phosphorylated, partially phosphorylated, or not phosphorylated depending on the host cell expressing said protein. Therefore, the same protein can have, for example 5 serines that are phosphorylated in E. coli, as well as 3 serines out of these 5 serines phosphorylated in E. coli which are phosphorylated in S. saccharomyces. The same serine/threonine can be phosphorylated in one host cell and not phosphorylated in another host cell. Therefore, it would be unclear as to which serines or threonines are “potentially phosphorylated” in a given dairy protein. For examination purposes, no patentable weight will be given to the term “potentially phosphorylated”. Correction is required.
Claim 4 is indefinite in the recitation of “…protein of claim 1 which when recombinantly expressed in a heterologous expression system, exhibits at least one of the following…” for the following reasons. The claim requires the protein to have functional characteristics that are dependent upon the expression system being used, thus making the determination of which proteins are included or excluded from the scope of the claim impossible. As explained above, a protein having the same amino acid sequence can be phosphorylated, partially phosphorylated, or not phosphorylated depending on the host cell expressing said protein. If, for example, a protein having amino acid sequence X when expressed in E. coli has capacity to bind calcium, and lacks the ability to bind calcium if expressed in S. cerevisiae, the same protein can be included or excluded from the scope of the claim depending on the expression system used. For examination purposes, no patentable weight will be given to the recited limitation and it will be assumed that claim 4 is as a duplicate of claim 1 as interpreted above. Correction is required.
Claim 5 is indefinite in the recitation of “… protein of claim 1 which when recombinantly expressed in a heterologous expression system exhibits at least one of the following: a) an improved capacity to bind calcium ….” for the following reasons. The claim requires the protein to have functional characteristics that are dependent upon the expression system being used, thus making the determination of which proteins are included or excluded from the scope of the claim impossible. As explained above, a protein having the same amino acid sequence can be phosphorylated, partially phosphorylated, or not phosphorylated depending on the host cell expressing said protein. The same protein when expressed in expression system X can meet the functional characteristics recited and at the same time not meet the functional characteristics recited if expressed in expression system Y. Therefore, the same protein can be included or excluded from the scope of the claim depending on the expression system used. For examination purposes, it will be assumed that claim 5 is as a duplicate of claim 1 as interpreted above. Correction is required.
Claim 6 is indefinite in the recitation of “…protein of claim 1 which apart from the modifications described is otherwise the same in sequence as the unmodified dairy protein” for the following reasons. It is unclear as to which are the modifications described. In addition, even if the “modifications described” refer to the replacement of potentially phosphorylated serines and/or threonines, for the reasons indicated above, the “modifications” are indefinite in view of the fact that the term “potentially phosphorylated amino acid” is unclear. Furthermore, the term “is otherwise the same in sequence as the unmodified dairy protein” is unclear in the absence of the sequence identifier associated with the unmodified dairy protein. Furthermore, the term is unclear because one cannot determine if the “modified dairy protein” is required to comprise all of the amino acid sequence of the unmodified dairy protein except for specific substitutions. For examination purposes, claim 6 will be interpreted as a duplicate of claim 1. Correction is required.
When amending the claims, applicant is advised to carefully review all examined claims and make the necessary changes to ensure proper antecedent basis and dependency.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
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, 3-6 and 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 pre-AIA 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 1, 3-6 and 15 are directed in part to a genus of polypeptides which are variants of a genus of dairy proteins, wherein said variants comprise an aspartic acid or a glutamate at a position corresponding to a position in the dairy proteins that comprises a serine or a threonine. Since there is no limit as to the number of modifications present in the variant so long as they have the recited substitutions, the claims are directed to a genus of variants of any dairy protein, wherein said variants can have any structure and activity. See Claim Rejections under 35 USC § 112(b) or Second Paragraph (pre-AIA ) below for claim interpretation.
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 no structural limitation with respect to the members of the genus of proteins required by the claims. While the specification in the instant application discloses the structure of a limited number of dairy proteins and variants of such dairy proteins having specific substitutions, it provides no clue as to the structural elements required in any dairy protein, nor does it teach which structural elements of the diary proteins disclosed, such as that of SEQ ID NO: 1, are required in any dairy protein from any mammalian organism. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which variants of any dairy protein that have the recited substitutions would have the same activity/function associated with dairy proteins.
The claims encompass a large genus of proteins which are structurally unrelated. 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, which features constitute a substantial portion of the genus. However, in the instant case, there is no recited structural feature which is representative of all the members of the genus of dairy proteins or variants of dairy proteins required by the claims, and there is no information as to which are the structural elements within the dairy proteins disclosed in the specification that are essential to maintain the same activity of a dairy protein. As known in the art, milk comprises a variety of proteins. Acquavia et al. (Molecules 30, 1994, pages 1-30, 2025) teach that milk is a complex and nutrient rich biological fluid (Introduction) and can comprise over 200 different proteins (page 3, 2.3 Proteins). One would recognize that the total number of dairy proteins is approximately 200 times the number of mammalian species, which is over 6500 with new species being discovered. Furthermore, while one could argue that the few dairy proteins and variants disclosed are representative of the structure of all the members of the genus of proteins required, it is noted that the art teaches several examples of how even highly structurally homologous polypeptides can have different enzymatic activities. For example, Witkowski et al. (Biochemistry 38:11643-11650, 1999) teach that one conservative amino acid substitution transforms a β-ketoacyl synthase into a malonyl decarboxylase and completely eliminates β-ketoacyl synthase activity. Tang et al. (Phil Trans R Soc B 368:20120318, 1-10, 2013) teach that two Dehalobacter reductive dehalogenases, CfrA and DcrA, having 95.2% sequence identity to teach other have exclusively different substrate (Abstract; page 7, left column, Discussion, CfrA and DcrA). Seffernick et al. (J. Bacteriol. 183(8):2405-2410, 2001) teach that two naturally occurring Pseudomonas enzymes having 98% amino acid sequence identity catalyze two different reactions: deamination and dehalogenation, therefore having different function. Therefore, since minor structural differences may result in changes affecting function, and no additional information correlating structure with the desired functional characteristics has been provided, one cannot reasonably conclude that the few species disclosed are representative of the structure of all the dairy proteins and variants required by the claims.
Due to the fact that the specification only discloses a limited number of species of the genus of dairy proteins and variants of said dairy proteins having the recited substitutions, and the lack of description of any additional species by any relevant, identifying characteristics or properties, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Claims 1, 3-6 and 15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for variants of the protein of SEQ ID NO: 1, wherein said variants comprise SEQ ID NO: 2, 3, 4, or 38, does not reasonably provide enablement for any dairy protein having any structure or any variant of said dairy protein having substitutions of threonine or serine residues with aspartate or glutamate residues. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breadth of the claims. The factors which have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breadth of the claims. Claims 1, 3-6 and 15 broadly encompass polypeptides which are variants of a genus of dairy proteins, wherein said variants comprise an aspartic acid or a glutamate at a position corresponding to a position in the dairy proteins that comprises a serine or a threonine. As explained above, in view of the fact that the there is no limit as to the number of modifications present in the variants, the claims are directed to variants of any dairy protein, wherein said variants can have any structure and activity. See Claim Rejections under 35 USC § 112(b) or Second Paragraph (pre-AIA ) below for claim interpretation.
The enablement provided is not commensurate in scope with the claims due to the extremely large number of proteins of unknown structure encompassed by the claims, the lack of information regarding the structural elements required in any dairy protein or any variant of said dairy protein that has the same activity as that of the dairy protein, and how to use those variants of unknown function. In the instant case, the specification enables variants of the protein of SEQ ID NO: 1, wherein said variants comprise SEQ ID NO: 2, 3, 4, or 38.
The amount of direction or guidance presented and the existence of working examples. The specification discloses the amino acid sequence of the proteins of SEQ ID NO: 2, 3, 4, and 38, as working examples. However, the specification fails to provide any clue as to the structural elements required in any dairy protein, nor does it teach which structural elements of the diary proteins disclosed, such as that of SEQ ID NO: 1, are required in any dairy protein from any mammalian organism. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which variants of any dairy protein that have the recited substitutions would have the same activity/function associated with dairy proteins.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. The amino acid sequence of a polypeptide determines its structural and functional properties. While the art discloses a limited number of dairy proteins, neither the specification nor the art provide a correlation between structure and function such that one of skill in the art can envision the structure of any dairy protein or any variant of a dairy protein that has the same activity of said dairy protein. The art clearly teaches that (a) determining function based solely on structural homology, and (b) modification of a protein’s amino acid sequence to obtain the desired activity without any guidance/knowledge as to which amino acids in a protein are tolerant of modification and which ones are conserved are highly unpredictable. For example, Singh et al. (Current Protein and Peptide Science 19(1):5-15, 2018) disclose different protein engineering approaches and state that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility and conformational changes (page 11, left column, last paragraph). Sadowski et al. (Current Opinion in Structural Biology 19:357-362, 2009) teach that much of the problem in assigning function from structure comes from functional convergence, where although a stable structure is required to perform many functions it is not always necessary to adopt a particular structure to carry out a particular function (page 357, right column, first full paragraph). Sadowski et al. further explain that the unexpected and significant difficulties of predicting function from structure show that the potential of structural models for providing novel functional annotations has not yet fully realized. Sadowski et al. also states that while a few successes have been achieved which required manual intervention, the ability to vary the requirements for specificity in prediction means that it is difficult to determine how useful the end result may be for the user (page 361, left column, first full paragraph). The teachings of Singh et al. and Sadowski et al. are further supported by the teachings of Witkowski et al., Tang et al. and Seffernick et al. already discussed above, where it is shown that even small amino acid changes result in activity changes.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. While methods of generating or isolating variants of a polypeptide and functional assays were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of proteins to find proteins with the same activities associated with dairy proteins, and find how to use those proteins which lack the activities associated with dairy proteins. In the absence of (i) a rational and predictable scheme for selecting those proteins most likely to have the desired functional features, and/or (ii) a correlation between structure and activity, one of skill in the art would have to test an essentially infinite number of proteins to determine which ones have the desired functional characteristics.
Therefore, taking into consideration the extremely broad scope of the claim, the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between structure and the desired function, and the high degree of unpredictability of the prior art in regard to structural changes and their effect on function, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims.
Claim Rejections - 35 USC § 102 (AIA )
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3-6 and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jebb et al. (GenBank accession number KAF6499636, 8/7/2020).
Claims 1, 3-6 and 15 as interpreted are directed in part to a polypeptide which is a variant of a dairy protein, wherein said variant comprises an aspartic acid or a glutamate at a position corresponding to a position in the dairy protein that comprises a serine or a threonine. The specification discloses the polypeptide of SEQ ID NO: 1 as a bovine A2 β-casein (dairy protein). Therefore, the claims encompass a protein which is a variant of the polypeptide of SEQ ID NO: 1, wherein said protein comprises an aspartic acid or a glutamate at a position corresponding to a position in the polypeptide of SEQ ID NO: 1 that comprises a serine or a threonine. See Claim Rejections under 35 USC § 112(b) or Second Paragraph (pre-AIA ) below for claim interpretation.
Jebb et al. disclose a β-casein that is a variant of the polypeptide of SEQ ID NO: 1 that comprises a substitution of a serine to an aspartate at the position corresponding to position 15 of the polypeptide of SEQ ID NO: 1. See underlined/bold/italicized residue in the alignment provided above. Please note that the term “a modified diary protein” is a product-by-process limitation and patentability of a product is determined by its structural characteristics. In the instant case, the protein of Jebb et al. meets the recited structural characteristics. Therefore, the protein of Jebb et al. anticipates the instant claims as written/interpreted.
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 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.
Claim Rejections - 35 USC § 103 (AIA )
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 of this title, 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 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.
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, 3-6 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Philip et al. (Plant Science 161:323-335, 2001) in view of Chen et al. (Endocrinology 139(2):609-616, 1998), Pearlman et al. (Cell 147:934-946, 2011), Clegg et al. (Protein Expression and Purification 67:23-34, 2009) and Bijl et al. (Journal of Dairy Science 97:7240-7246, 2014).
Philip et al. teach the production of bovine β-casein in a transgenic soybean plant (Abstract). Philip et al. tech that bovine β-casein is a phosphoprotein that is modified post-translationally by the covalent coupling of five phosphate groups to serine residues at the N-terminus of this protein (phosphorylation; page 332, left column). Philip et al. teach that the phosphoserine residues of the bovine β-casein play an essential role in the formation of casein micelles via Ca2+-phosphate clusters and also contribute to increased curd tension during cheese making (page 332, left column). Philip et al. teach that bovine β-casein has been expressed in several heterologous organisms such as E. coli and S. cerevisiae but phosphorylation was not observed in E. coli (page 332, right column, last full paragraph). Philip et al. teach that the bovine β-casein in the transgenic soybean plant was not phosphorylated (page 332, right column, first full paragraph). Bijl et al. teach that in caseins, phosphorylation is one of the key factors responsible for the stabilization of calcium phosphate nanoclusters in casein micelles and the internal structure of casein micelles. Bijl et al. teach that the micellar structure in caseins allows milk to deliver large amounts of calcium and phosphate to the neonate (page 7240, right column, second full paragraph). Clegg et al. teach that while it has been possible to obtain the physiological phosphorylation of human β-casein in E. coli by co-expressing a casein kinase 2 (CK2), it was not possible to obtain the same outcome with bovine β-casein under comparable conditions (page 32, left column, first full paragraph). Pearlman et al. teach that protein phosphorylation adds a negative charge to amino acid side chains and that negatively charged amino acids, namely aspartate and glutamate can mimic the phosphorylated state of a protein (page 934, left column Summary). Pearlman et al. teach that most eukaryotic protein phosphorylation occurs at serine, threonine and tyrosine residues (page 934, left column, Introduction) Pearlman et al. teach that phosphorylation sites have evolved from glutamate and aspartate (Abstract). Chen et al. teach the replacement of a serine that is phosphorylated in human prolactin (PRL) with either glutamate or aspartate to mimic the phosphorylated human prolactin (page 609, right column, first full paragraph). Chen et al. teach that their molecular mimic of the phosphorylated human PRL as well as the phosphorylated human hormone are very effective in antagonizing growth promotion in response to unmodified hormone, thus showing that the variant clearly mimics the phosphorylated hormone (page 615, left column, second full paragraph). Chen et al. teach that molecular mimicry of phosphorylation has been successfully applied to a variety of enzymes and that structural changes observed after phosphorylation have been also reproduced with aspartate mutants (page 615, left column, first full paragraph). Chen et al. teach that the production of a recombinant mimic of a phosphorylated hormone has several advantages, including the ability of producing large amounts of the protein entirely free from the non-phosphorylated counterpart, and the lack of dephosphorylation over time (page 615, third full paragraph). Chen et al. do not teach a bovine β-casein or a dairy protein.
Claims 1, 3-6 and 15 as interpreted are directed in part to a polypeptide which is a variant of a dairy protein, wherein said variant comprises an aspartic acid or a glutamate at a position corresponding to a position in the dairy protein that comprises a serine or a threonine. See Claim Rejections under 35 USC § 112(b) or Second Paragraph (pre-AIA ) below for claim interpretation.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to replace serine residues in the bovine β-casein of Philip et al. which are phosphorylated when produced in cow milk with aspartate or glutamate. A person of ordinary skill in the art is motivated to make such substitution for the benefit of producing a mimicry of the phosphorylated bovine β-casein which can be produced in large amounts consistently in different recombinant host cells independent of their ability to phosphorylate the bovine β-casein, without the presence of non-phosphorylated byproducts, and without concerns regarding dephosphorylation over time. One of ordinary skill in the art has a reasonable expectation of success at making such substitution and obtaining a functional equivalent of the phosphorylated bovine β-casein because the molecular biology methods to make substitutions in a protein are well known in the art as evidenced by Chen et al., and the prior art teaches the use of these substitutions in proteins that are phosphorylated in their native environments to mimic phosphorylation as evidenced by Pearlman et al. and Chen et al. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention
Conclusion
No claim is in condition for allowance.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
July 10, 2026
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