Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
1. Applicant’s election of Group I (claims 1-5, species sequence of SEQ ID Nos. 5 & 6) in the reply filed on 12/18/25 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
2. Claims withdrawn:
Claims 6-15 and non-elected sequences of SEQ ID Nos. SEQ ID NO: 7, SEQ ID NO: 21, SEQ ID NO: 23 and SEQ ID NO: 25; and SEQ ID NO: 8, SEQ ID NO: 22, SEQ ID NO: 24 and SEQ ID NO: 26 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
3. Priority
Applicant’s claim for domestic priority under 35 U.S.C. 119(e), filed 2/19/21 & 4/3/21, is acknowledged.
4. Drawings
The drawings filed on 8/17/23 are acknowledged.
5. Specification
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
6. 35 U.S.C. § 112, first paragraph (Written Description)
Claims 1-5 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.
Claims 1-5 are drawn to the following genus claims:
1. A non-naturally occurring carbonic anhydrase comprising at least one mutation that results in the substitution of at least one cysteine for at least one amino acid in a naturally occurring carbonic anhydrase; and wherein the non-naturally occurring carbonic anhydrase has increased activity at a temperature of greater than about 60 degrees Celsius when compared to the naturally occurring carbonic anhydrase.
2. The non-naturally occurring carbonic anhydrase of claim 1 wherein the increased activity is for more than about 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 24 hours, 44 hours, 48 hours, and 92 hours.
3. The non-naturally occurring carbonic anhydrase of claim 1 wherein the increased activity is at a temperature greater than 65, 70, 75, 80, 85 or 90 degrees Celsius.
4. The non-naturally occurring carbonic anhydrase of claim 1 wherein a nucleotide sequence encoding the non-naturally occurring carbonic anhydrase comprises a sequence that is greater than 70% identical to a sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 22, SEQ ID NO: 24 and SEQ ID NO: 26.
5. The non-naturally occurring carbonic anhydrase of claim 1 comprising an amino acid sequence that is greater than 70% identical to a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 21, SEQ ID NO: 23 and SEQ ID NO: 25.
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.
The specification, however, does not provide description of carbonic anhydrase from any source and structure comprising at least one mutation at any cysteine position that results in the substitution of at least one cysteine for at least any one amino acid in a naturally occurring carbonic anhydrase; and wherein the non-naturally occurring carbonic anhydrase has increased activity at a temperature of greater than about 60 degrees Celsius when compared to the naturally occurring carbonic anhydrase.
The specification, however, only provides description of a few species of DNA including SEQ ID NO: 6 (SEQ ID NO: 8 being the other DNA sequence having a close sequence homology of 98.5% to SEQ ID NO: 6); encoding a carbonic anhydrase mutant from B. licheniformis of SEQ ID NO: 5 (SEQ ID NO: 7 being the other protein sequence having a close sequence homology of 98.3% to SEQ ID NO: 5).
The specification does not contain any disclosure or description of the structure and function of all DNA/protein sequences that are at least 70% identical to SEQ ID NO: 6/5, or a derivative derived from such a sequence(s) by insertion, deletion or substitution, and encoding a protein which has the biological activity of a carbonic anhydrase.
The 5 species disclosed from B. licheniformis are not representative of the genus claimed. According to MPEP 2163, to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v.Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed.Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The scope of each genus includes many members of carbonic anhydrase enzymes with widely differing structural, chemical, and physical characteristics. Furthermore, each genus is highly variable because a significant number of structural differences between genus members exit. The specification does not describe and define any structural features and amino acid sequences commonly possessed by each genus. There is no art-recognized correlation between any structure of a carbonic anhydrase and sequences having varying sequence homology, i.e., 70% of SEQ ID NO: 5/6. Those of ordinary skill in the art would not be able to identify without further testing what specific DNA sequences would encode a protein having carbonic anhydrase activity.
The genus of polynucleotides/DNA/protein from any source and varying mutations of cysteine residues or the sequences of amino acid/DNA at least 70% identical to SEQ ID NO: 5/6 that comprise these DNA/protein molecules and encoding many different proteins may be obtained with the aid of a computer by a skilled artisan. However, there is no teaching regarding which 30% of the sequence that can be varied and still result in a DNA encoding a protein having carbonic anhydrase activity. An important consideration is that structure is not necessarily a reliable indicator of function. The instant specification provides no disclosure relating similarity or identity of structure to conservation of function. General knowledge in the art provides guidance to modification of some amino acids that are tolerated without losing a protein’s tertiary structure.
The genus of polypeptides and the encoding polynucleotides and modifications required in the claimed invention is an extremely large structurally and functionally variable genus. While the argument can be made that the recited genus of polypeptides is adequately described by the disclosure of the structures of SEQ ID NO: 5/6 (for example), with specific structures having the associated function/activity, since one could use structural homology to isolate those polypeptides and the encoding polynucleotides recited in the claims. The art clearly teaches the “Practical Limits of Function Prediction”:
(a) Devos et al., (Proteins: Structure, Function and Genetics, 2000, Vol. 41: 98-107), teach that the results obtained by analyzing a significant number of true sequence similarities, derived directly from structural alignments, point to the complexity of function prediction. Different aspects of protein function, including (i) enzymatic function classification, (ii) functional annotations in the form of key words, (iii) classes of cellular function, and (iv) conservation of binding sites can only be reliably transferred between similar sequences to a modest degree. The reason for this difficulty is a combination of the unavoidable database inaccuracies and plasticity of proteins (Abstract, page 98) and the analysis poses interesting questions about the reliability of current function prediction exercises and the intrinsic limitation of protein function prediction (Column 1, paragraph 3, page 99) and conclude that “Despite widespread use of database searching techniques followed by function inference as standard procedures in Bioinformatics, the results presented here illustrate that transfer of function between similar sequences involves more difficulties than commonly believed. Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, page 105). Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, page 105). Applicants’ are respectfully directed to the problems associated EC Classification in the section “Transferring the EC Classification enzyme to Non-Enzyme Comparisons”; pages 101-102 and Fig. 2a)-b), highlighting the structural and functional heterogeneity based on EC Classification numbers; as the stereo-specificity, substrate-specificity and catalytic properties vary widely.
(b) Whisstock et al., (Quarterly Reviews of Biophysics 2003, Vol. 36 (3): 307-340) also highlight the difficulties associated with “Prediction of protein function from protein sequence and structure”; “To reason from sequence and structure to function is to step onto much shakier ground”, closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function, in such cases, assignment of function on the basis of homology, in the absence of direct experimental evidence, will give the wrong answer (page 309, paragraph 4), it is difficult to state criteria for successful prediction of function, since function is in principle a fuzzy concept. Given three sequences, it is possible to decide which of the three possible pairs is most closely related. Given three structures, methods are also available to measure and compare similarity of the pairs. However, in many cases, given three protein functions, it would be more difficult to choose the pair with most similar function, although it is possible to define metrics for quantitative comparisons of different protein sequences and structures, this is more difficult for proteins of different functions (page 312, paragraph 5), in families of closely related proteins, mutations usually conserve function but modulate specificity i.e., mutations tend to leave the backbone conformation of the pocket unchanged but to affect the shape and charge of its lining, altering specificity (page 313, paragraph 4), although the hope is that highly similar proteins will share similar functions, substitutions of a single, critically placed amino acid in an active-site residue may be sufficient to alter a protein’s role fundamentally (page 323, paragraph 1).
(c) This finding is reinforced in the following scientific teachings for specific proteins in the art that suggest, even highly structurally homologous polynucleotides and encoded polypeptides do not necessarily share the same function. For example, Witkowski et al., (Biochemistry 38:11643-11650, 1999), teaches that one conservative amino acid substitution transforms a b-ketoacyl synthase into a malonyl decarboxylase and completely eliminates b-ketoacyl synthase activity.
The claim includes a genus that can be analyzed at several levels sequentially for the purpose of focusing the issue. First, the disclosure of SEQ ID NO: 5/6 combined with pre-existing knowledge in the art regarding the genetic code and its redundancies would have put one in possession of the genus of nucleic acids that encode SEQ ID NO: 5 (the encoding protein). With the aid of a computer, one of skill in the art could identify all of the nucleic acid sequences with at least 70% sequence identity with SEQ ID NO: 5/6. However, there is no teaching regarding which 30% of the amino acids can vary from SEQ ID NO: 5/6 and still result in a protein that retains carbonic anhydrase activity. Further, there is no disclosed or art-recognized correlation between any structure other than SEQ ID NO: 5 and carbonic anhydrase activity. An important consideration is that structure is not necessarily a reliable indicator of function. In this example, there is no disclosure relating similarity of structure to conservation of function. General knowledge in the art included the knowledge that some amino acid variations are tolerated without losing a protein’s tertiary structure. The results of amino acid substitutions have been studied so extensively that amino acids are grouped in so-called “exchange groups” of similar properties because substituting within the exchange group is expected to conserve the overall structure. For example, the expectation from replacing leucine with isoleucine would be that the protein would likely retain its tertiary structure. On the other hand, when non-exchange group members are substituted, e.g., proline for tryptophan, the expectation would be that the substitution would not likely conserve the protein’s tertiary structure. Given what is known in the art about the likely outcome of substitutions on structure, those in the art would have likely expected the applicant to have been in possession of a genus of proteins having a tertiary structure similar to SEQ ID NO: 5 although the claim is not so limited. However, conservation of structure is not necessarily a surrogate for conservation of function. In this case, there is no disclosed correlation between structure and function. There is no disclosure of the active site amino acid residues responsible for the catalytic activity. Claims 1-3 are further complicated as no reference is made to any structure or proposed modification(s). While general knowledge in the art may have allowed one of skill in the art to identify other proteins expected to have the same or similar tertiary structure, in this case there is no general knowledge in the art about similar proteins to SEQ ID NO: 5 to suggest that general similarity of structure confers the activity. Accordingly, one of skill in the art would not accept the disclosure of SEQ ID NO: 5 (or the encoding DNA of SEQ ID NO: 6) as representative of other proteins having carbonic anhydrase activity or mutational modifications thereof. The specification, taken with the pre-existing knowledge in the art of amino acid substitution and the genetic code, fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph.
7. 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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-3 is/are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by US 2015/0191711 A1.
[0002] Carbonic anhydrases (CA, EC 4.2.2.1) is a group of enzymes that catalyzes the reversible reaction of carbon dioxide and water into bicarbonate and proton according to:
CO.sub.2+H.sub.2O.revreaction.HCO.sub.3.sup.-+H.sup.+
[0072] "Carbonic anhydrase" and the abbreviation "CA" is used interchangeably to refer to a polypeptide having enzymatic E.0 4.2.1.1 activity and that is capable of catalyzing the inter-conversion of carbon dioxide and water to bicarbonate and a proton.
[0073] "Human carbonic anhydrase II" and "HCA II" is used interchangeably to denote the iso-form 2 variant of human carbonic anhydrase II.
In [0024] & [0025], US 2015/0191711 A1 teaches a carbonic anhydrase which is simple and economical to produce, has a high catalytic activity, a high physical stability as determined by thermodynamic, thermal and kinetic stability and a long life time under various conditions. The reference further teaches way to achieve invention by means of the isolated polypeptide having carbonic anhydrase activity, the sequence of which is modified human carbonic anhydrase II, wherein the polypeptide comprises the mutations A23C, S99C, L202C, C205S and V241C, has increased physical stability, high enzyme activity compared to wild type carbonic anhydrase II and further comprises disulfide bridges between C23 and C202 and/or between C99 and C241. [0101] The increased thermal, thermodynamic and kinetic stability of the double disulfide bridge variant of SEQ ID NO: 8 should render it a high life time at elevated temperatures.
"The esterase activity of the three disulfide variants (SEQIDNO: 4, 6 and 8) at the conditions of measurement (approx.21C.) was found to be 99, 86 and 78 percent respectively, compared to the activity of the HCAII pwt variant; para [0096]. See tables 3-5 and Example 10.
Regarding claim 2, the reference discloses the non-naturally occurring carbonic anhydrase of claim1, and further discloses wherein the increased activity is for more than about 30 minutes, 1hour, 2hours, 3hours, 4hours, 5hours, 6hours, 24hours, 44hours, 48hours, and 92hours(para[0096];Tables3-4; para [0101]-[0102]- "The increased thermal, thermodynamic and kinetic stability of the doubled disulfide bridge variant of SEQ ID NO: 8 should render it a high life time at elevated temperatures....the half-life (1/2) of each enzyme variant a teach temperature can be calculated by t1/2=In2/k. The results of the life time experiments are presented in table 7-9 and FIG.7."; Table7-“Percent remaining esterase activity after 15 min incubation...Variant...Temperature...SEQIDNO: 2...60[C]...1[%]...SEQIDNO:8...60[C]...99[%]";Table 8-"Percent remaining esterase activity after 2h incubation...Variant...Temperature...SEQIDNO:2...60 [C]...O[%]...SEQIDNO:8...6O[C]...106[%]";Table 9-"Inactivation rate constants (ku) inactivation, halftime (t1/2) and t/10 of enzyme variants at 60-70C...Variant...Temperature.. .t1/2...SEQIDNO: 8...60[C]...2057 (86days)"; Note, as wild-type equivalent variant SEQIDNO: 2 displays 0% activity after 2h at 6OC and half-life of variant SEQIDNO:8 at 60C is~86days, the latter variant exhibits increased activity at all time points in between). Regarding claim 3, the reference discloses the non-naturally occurring carbonic anhydrase of claim 1, and the reference further discloses wherein the increased activity is at a temperature greater than 65, 70, 75, 80, 85 or 90 degrees Celsius (para[0096];Tables 3-4).
8. No claim is allowed.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to TEKCHAND SAIDHA whose telephone number is (571)272-0940. The examiner can normally be reached on M-F 8.00-5.30. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B Mondesi can be reached on 408 918 7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TEKCHAND SAIDHA/
Primary Examiner, Art Unit 1652
Recombinant Enzymes, Hoteling
Telephone: (571) 272-0940
Fax: (571) 273-0940