DETAILED ACTION
Status of the Application
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 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 of claims 3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 and cancellation of claims 4, 10-13, 15, 17, 19-20, 22-23, 25, 27, 30, 32-35, 39 as submitted in a communication filed on 10/24/2023 is acknowledged.
Priority
Acknowledgment is made of a claim for domestic priority under 35 U.S.C. 119(e) to provisional application No. 63/105,052 filed on 10/23/2020.
This is the US national application which entered the national stage from PCT/US2021/055991 filed on 10/21/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/24/2023, 1/26/2024, 5/23/2024 and 3/18/2025 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings submitted on 4/20/2023 have been reviewed and are accepted by the Examiner for examination purposes.
Claim Objections
Claim 1 is objected to due to the recitation of “(i) (1) the aliquot…(2) the aliquot….(3) the aliquot….or (4) the aliquot….(ii) (1) the aliquot comprises….(2) the aliquot comprises…or (iii) (1) the aliquot comprises… ”. Sections (i), (ii) and (iii) each provide several options in the alternative which are all limiting the TSAC concentration of the aliquot and the duration of the filtration step. Therefore, all the options in (i), (ii) and (iii) could be combined in a list of 10 options (e.g., options (i)-(x)) instead of three lists (e.g., (i), (ii) and (iii)). In addition, since Arabic numerals are used for claim numbering, to avoid confusion, these labels should be replaced with different labels (e.g., (I)..(X), (i)-(x), etc.) Appropriate correction is required.
Claim 38 is indefinite in the recitation of “…amino acid sequence having at least 90% or 100% sequence identity to the sequence set forth in SEQ ID NO: 1”. To enhance clarity and to be consistent with commonly used claim language, the term should be amended to recite “…amino acid sequence having at least 90% or 100% sequence identity to the sequence of SEQ ID NO: 1”. Appropriate correction is required.
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, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 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 is indefinite in the recitation of “obtaining an aliquot from the aqueous culture medium at from about 6 to about day 10 after inoculation….(f) performing at least one purification step to obtain a bulk drug solution (BDS); wherein ….the aliquot comprises a TSAC concentration of less than about X mol/mol and the filtration step is held for less than about A hours…...the aliquot comprises a TSAC concentration of from about X mol/mol to about Y mol/mol and the filtration step is held from about A hours to about B hours….the aliquot comprises a TSAC concentration of greater than about X mol/mol…the aliquot comprises a TSAC concentration of less than or equal to about X mol/mol… the aliquot comprises a TSAC concentration of greater than or equal to about X mol/mol..” for the following reasons.
There is no antecedent basis for “the filtration step”. Therefore, it is unclear as to how limitations regarding the filtration step further limit the claimed method.
The term “from about to….about…” is unclear for the following reasons. The term “about” encompasses a range which includes values which are higher and lower than the recited reference value (e.g., 6 days, 10 days, 2.5 mol/mol, etc.). The term “from X to Y”, implies a range where X and Y are the endpoints. Therefore, in the absence of a clear definition of what is encompassed by the term “about”, the term "from about X to about Y" is unclear and confusing because X and Y are endpoints which are undefined ranges.
The term “greater than about…” and “less than about” are unclear for the following reasons. The term “greater than” implies that only values higher than the recited reference value are encompassed. The term “less than” implies that only values lower than the recited reference value are encompassed. Therefore, in the absence of a clear definition of what is encompassed by the term “about”, the term "greater than about" is unclear and confusing since the term refers to values which are higher than undefined values which are either higher or lower than the recited reference value, and the term “less than about” is unclear and confusing since the term refers to values which are lower than undefined values which are either higher or lower than the recited reference. In essence, the terms eliminate the relevance of the recited reference points because the reference values associated with “greater than” and “less than” are variable and undefined.
The terms “less than or equal to about..” and “greater than or equal to about..” are unclear for the following reasons. The term “greater than” implies that only values higher than the recited reference value are encompassed. The term “less than” implies that only values lower than the recited reference value are encompassed. The term “equal” implies that only values that are identical to the recited reference value are encompassed. Therefore, in the absence of a clear definition of what is encompassed by the term “about”, the term "greater than or equal to about.. " is unclear and confusing since the term refers to values which are higher or equal to undefined values which are either higher or lower than the recited reference value, and the term “less than or equal to about” is unclear and confusing since the term refers to values which are lower or equal to undefined values which are either higher or lower than the recited reference. In essence, the terms eliminate the relevance of the recited reference points because the reference values associated with “greater than or equal to” and “less than or equal to” are variable and undefined.
In addition, as written, it is unclear as to what should be the subject of the purification step (i.e., what is purified?). Moreover, it is unclear as to what a bulk drug solution is or what it comprises. Furthermore, it is unclear as to how step (f) is related to the preamble of the claim where it is stated that the method is a method for producing a recombinant alkaline phosphatase. For examination purposes, no patentable weight will be given to the terms “from about day 6 to about day10” and “(f) performing at least one purification step….about 40 hours to about 48 hours”. Correction is required.
Claim 3 is indefinite in the recitation of “wherein the filtration step comprises…” for the following reasons. There is no antecedent basis for the filtration step in claim 1, from which claim 3 depends. For examination purposes, no patentable weigh will be given to the term “wherein the filtration step comprises…”. Correction is required.
Claim 6 is indefinite in the recitation of “wherein the TSAC concentration of the aliquot is less than about 2.5 mol/mol and the filtration step is held for less than about nine hours” for the following reasons. The term “less than” implies that only values lower than the recited reference value are encompassed. Therefore, in the absence of a clear definition of what is encompassed by the term “about”, the term “less than about” is unclear and confusing since the term refers to values which are lower than undefined values which are either higher or lower than the recited reference. In essence, the terms eliminate the relevance of the recited reference points because the reference values associated with “less than” are variable and undefined. In addition, there is no antecedent basis for the filtration step in claim 1, from which claim 6 depends. For examination purposes, claim 6 will be interpreted as a duplicate of claim 1. Correction is required.
Claim 7 is indefinite in the recitation of “wherein the TSAC concentration of the aliquot is from about 2.5 mol/mol to about 2.7….the filtration step is held for about 10 hours to about 14 hours” for the following reasons. The term “about” encompasses a range which includes values which are higher and lower than the recited reference value (e.g., 10 hours, 2.5 mol/mol, etc.). The term “from X to Y”, implies a range where X and Y are the endpoints. Therefore, in the absence of a clear definition of what is encompassed by the term “about”, the term "from about X to about Y" is unclear and confusing because X and Y are endpoints which are undefined ranges. In addition, there is no antecedent basis for the filtration step in claim 1, from which claim 7 depends. For examination purposes, claim 7 will be interpreted as a duplicate of claim 1. Correction is required.
Claim 8 is indefinite in the recitation of “wherein the alkaline phosphatase concentration during the filtration step is about 1.8 g/L to about 5.0 g/L; and/or the TSAC concentration of the BDS is about 1.2 mol/mol to about 3.0 mol/mol” for the following reasons. The term “about” encompasses a range which includes values which are higher and lower than the recited reference value (e.g., 1.8 g/L, 1.2 mol/mol, etc.). The term “is X to Y”, implies a range where X and Y are the endpoints. Therefore, in the absence of a clear definition of what is encompassed by the term “about”, the term "is about X to about Y" is unclear and confusing because X and Y are endpoints which are undefined ranges. In addition, there is no antecedent basis for the filtration step in claim 1, from which claim 8 depends. Therefore, one cannot determine which is the solution that has the alkaline phosphatase concentration recited. Moreover, there is no indication in claim 1 that the bulk drug solution has a total sialic acid content. For examination purposes, claim 8 will be interpreted as a duplicate of claim 1. Correction is required.
Claim 9 is indefinite in the recitation of “wherein the alkaline phosphatase concentration during the filtration step is about….and/or the TSAC concentration of the BDS is about 1.6 mol./mol to about 2.4 mol/mol” for the following reasons. The term “about” encompasses a range which includes values which are higher and lower than the recited reference value (e.g., 1.8 g/L, 1.6 mol/mol, etc.). The term “is X to Y”, implies a range where X and Y are the endpoints. Therefore, in the absence of a clear definition of what is encompassed by the term “about”, the term "is about X to about Y" is unclear and confusing because X and Y are endpoints which are undefined ranges. In addition, there is no antecedent basis for the filtration step in claim 1, from which claim 9 ultimately depends. Therefore, one cannot determine which is the solution that has the alkaline phosphatase concentration recited. Moreover, there is no indication in claim 1 that the bulk drug solution has a total sialic acid content. For examination purposes, claim 9 will be interpreted as a duplicate of claim 1. Correction is required.
Claim 14 is indefinite in the recitation of “wherein the filtration step is held at a constant temperature of about 15 C to about 25 C” for the following reasons. There is no antecedent basis for the filtration step in claim 1, from which claim 14 depends. For examination purposes, claim 14 will be interpreted as a duplicate of claim 1. Correction is required.
Claim 16 is indefinite in the recitation of “wherein the temperature is about 22 C” for the following reasons. There is no antecedent basis for the filtration step in claim 1, from which claim 16 ultimately depends. Therefore, it is unclear as to which is the step where the temperature is held at about 22 C”. For examination purposes, claim 16 will be interpreted as a duplicate of claim 1. Correction is required.
Claim 18 is indefinite in the recitation of “wherein the aliquot is from about 1 ml to about 500 ml” for the following reasons. The term “about” encompasses a range which includes values which are higher and lower than the recited reference value (e.g., 1 ml, 500 ml). The term “from X to Y”, implies a range where X and Y are the endpoints. Therefore, in the absence of a clear definition of what is encompassed by the term “about”, the term "from about X to about Y" is unclear and confusing because X and Y are endpoints which are undefined ranges. For examination purposes, no patentable weight will be given to the term. Correction is required.
Claim 24 is indefinite in the recitation of “wherein the chromatography column comprises a Protein A column” for the following reasons. As written, it is unclear as to how a chromatography column can have another column. Is the chromatography column a system of several columns? For examination purposes, it will be assumed that the claim reads “wherein the chromatography column is a Protein A column”. Correction is required.
Claim 26 is indefinite in the recitation of “wherein step (c) further comprises performing a buffer exchange and/or concentrating the alkaline phosphatase” for the following reasons. As written, it is unclear as to which is the solution subjected to a buffer exchange. Is a buffer exchange required for the aliquot prior to centrifuging? Is a buffer exchange required for the supernatant after centrifugation? In addition, it is unclear as to which is the solution where the alkaline phosphatase is going to be concentrated. Is the concentration applied to the aliquot prior to centrifugation? Is the concentration applied to the supernatant after centrifugation? Is the concentration applied to the alkaline phosphatase containing solution obtained from the chromatography column? For examination purposes, claim 26 will be interpreted as a duplicate of claim 21. Correction is required.
Claim 29 is indefinite in the recitation of “…further comprising lyophilizing the alkaline phosphatase” for the following reasons. As written, it is unclear which is the solution containing alkaline phosphatase that should be lyophilized. Does it refer to lyophilization of the aqueous culture medium obtained in step (e)? For examination purposes, it will be assumed that claim 29 is a duplicate of claim 1. Correction is required.
Claim 36 is indefinite in the recitation of “wherein the culture medium is selected from the group consisting of EX-CELL® 302 Serum-free medium, CD DG44 medium, BD SELECT® medium, SFM4CHO medium, and combinations thereof” for the following reasons. There is no antecedent basis for the culture medium. It is noted that the only reference to a medium is the aqueous culture medium that comprises the recombinant alkaline phosphatase of step (b). In addition, the claim recites trademarks.
As set forth in MPEP § 2173.05(u), if a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 USC § 112(b) or pre-AIA 35 USC § 112, second paragraph. Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used to properly identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. In fact, the value of a trademark would be lost to the extent that it became descriptive of a product, rather than used as an identification of a source or origin of a product. The use of a trademark or a trade name in a claim to identify or describe a material or product would not only render a claim indefinite, but would also constitute an improper use of the trademark or trade name. For examination purposes, claim 36 will be interpreted as a duplicate of claim 1. Correction is required.
Claim 37 is indefinite in the recitation of “…is absent or is an amino acid sequence of at least one amino acid…” for the following reasons. It is unclear as to how one could have an amino acid sequence of one amino acid. For examination purposes, it will be assumed that the term reads “…is absent, or is at least one amino acid”. 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, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 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, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 are directed in part to a method which requires a genus of alkaline phosphatases and fusion proteins that comprise alkaline phosphatases, wherein said alkaline phosphatases have any structure. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) 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 regard to the members of the genus of enzymes required by the claimed method. While the specification discloses a fusion comprising a soluble human alkaline phosphatase (SEQ ID NO: 1), the specification fails to disclose the structure of additional recombinant alkaline phosphatases. There is no disclosure of the structural elements required in any alkaline phosphatase or the structural elements in the one alkaline phosphatase disclosed that should be present in any alkaline phosphatase. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize which proteins are alkaline phosphatases.
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 enzymes recited in the claims. Furthermore, even if the argument is made that the only alkaline phosphatase disclosed is representative of all of the members of the genus of alkaline phosphatases required by the claims, 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, in view of the fact that minor structural differences may result in changes affecting function, and no additional information correlating structure with the desired functional characteristics has been provided, one could have not reasonably concluded that the species disclosed is representative of the structure of all the alkaline phosphatases required by the claimed method.
Due to the fact that the specification has disclosed one species of the genus of alkaline phosphatases required by the claims, 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, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 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 a method for producing of the protein of SEQ ID NO: 1, does not reasonably provide enablement for a method for producing any alkaline phosphatase. 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, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 broadly encompass a method for producing alkaline phosphatases having any structure. The enablement provided is not commensurate in scope with the claims due to the lack of information regarding the structural elements required in any alkaline phosphatase, including those structural elements within the polypeptide of SEQ ID NO: 1 that are required in any alkaline phosphatase. In the instant case, the specification enables a method for producing the protein of SEQ ID NO: 1.
The amount of direction or guidance presented and the existence of working examples. The specification discloses the amino acid sequence of the protein of SEQ ID NO: 1, as a working example. However, the specification fails to provide any clue as to the structural elements required in any alkaline phosphatase, including those structural features within SEQ ID NO: 1 that should be present in any alkaline phosphatase. No correlation between structure and function has been presented.
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 alkaline phosphatases, 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 alkaline phosphatase. 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 enzymatic 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 enzymatic 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 a protein with alkaline phosphatase activity. 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 [enzyme] 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.
(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.
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Godawat et al. (WO 2019/190752 published 10/3/2019; cited in the IDS).
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 are directed in part to a method for producing a recombinant alkaline phosphatase, wherein said recombinant alkaline phosphatase has at least 90% sequence identity to the polypeptide of SEQ ID NO: 1, wherein said method comprises inoculating a bioreactor having a volume of at least 2 L to 20000 L with a CHO cell that expresses the recombinant alkaline phosphatase, obtaining an aqueous culture medium comprising the recombinant alkaline phosphatase, obtaining an aliquot from the aqueous culture medium to determine the total sialic content (TSAC) molar concentration per mole of the recombinant alkaline phosphatase in the aliquot, and harvesting the aqueous culture medium, wherein the determination of TSAC requires acid hydrolysis to release the TSAC, wherein the aliquot is centrifuged and the supernatant removed. Please note that the use of a chromatography column is optional. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
Godawat et al. a method for the production of an alkaline phosphatase (e.g., asfotase alfa) by inoculating a cell culture medium with CHO cells that express said alkaline phosphatase, and harvesting the cell culture medium after the desired cell density has been reached (pages 49-50, Example 1, paragraph [0166]). Godawat et al. teach that asfotase alfa is fusion glycoprotein that comprises the catalytic domain of a human alkaline phosphatase, an Fc domain, and a deca-aspartate peptide (page 2, paragraph [0005]) and comprises SEQ ID NO: 1 (page 3, paragraph 008]), which is identical to the protein of SEQ ID NO: 1 of the instant application. See alignment below. Godawat et al. teach that prior studies suggested that delaying harvesting time was associated with viability and TSAC decline and that the alkaline phosphatase is harvested at different time points such as 200 hours (8 days) or 12 days (page 38, paragraph [0131]). Godawat et al. teach that during manufacturing, the TSAC content is an important value and is monitored closely and that identification and quantitation of sialic acid in asfotase alfa samples at various stages of manufacture was performed by HPAE-PAD (page 50, paragraph [00168]), including before and after harvest (page 51, Example 2, paragraph [0171]; page 58, Example 5). Godawat et al. teach purification of samples taken for TSAC determination with a protein A column (page 58, paragraph [00188]). Godawat et al. teach the use of acid hydrolysis for determination of TSAC (page 39, paragraph [0134]). Godawat et al. teach the harvested culture medium is obtained by centrifugation and filtration to remove solids and cell debris (page 50, paragraph [01666]; page 17, paragraph [0073]). Therefore, it follows that the samples from the harvested culture medium used to determine TSAC have been centrifuged and the supernatant removed prior to TSAC determination. Godawat et al. teach that the harvested culture medium has a TSAC of 2.1 mol/mol to about 4.3 mol/mol (page 41, paragraph [00143]). Godawat et al. teach that the bioreactor can have a volume of 0.25 L to 25000 L (page 62, claims 10-12). Godawat et al. teach that the inoculated medium can be EX-CELL® 302 serum free medium, CD DG44 medium, or SFM4CHO medium (page 62, claim 9). Godawat et al. teach lyophilization of the purified alkaline phosphatase (page 40, paragraph [0139]). Therefore, the teachings of Godawat et al. anticipate the instant claims as written/interpreted.
SEQ ID NO: 1
BGT49563
ID BGT49563 standard; protein; 726 AA.
XX
AC BGT49563;
XX
DT 31-OCT-2019 (first entry)
XX
DE Recombinant alkaline phosphatase fusion protein (Asfotase alfa), SEQ 1.
XX
KW Alkaline phosphatase; Asfotase alfa; IgG1; Immunoglobulin G1;
KW bone disease; enzyme deficiency; enzyme production; fusion protein;
KW hypophosphatasia; metabolic-gen.; osteopathic; protein therapy;
KW recombinant protein; therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Modified-site 123
FT /note= "Asn is glycosylated"
FT Modified-site 213
FT /note= "Asn is glycosylated"
FT Modified-site 254
FT /note= "Asn is glycosylated"
FT Modified-site 286
FT /note= "Asn is glycosylated"
FT Modified-site 413
FT /note= "Asn is glycosylated"
FT Region 486..487
FT /note= "Linker"
FT Modified-site 564
FT /note= "Asn is glycosylated"
FT Region 715..716
FT /note= "Linker"
XX
CC PN WO2019190752-A1.
XX
CC PD 03-OCT-2019.
XX
CC PF 13-MAR-2019; 2019WO-US022102.
XX
PR 30-MAR-2018; 2018US-0650583P.
XX
CC PA (ALXI ) ALEXION PHARM INC.
XX
CC PI Godawat R, Dewitt M, Sui S, Rajendran S;
XX
DR WPI; 2019-83283W/00.
XX
CC PT Producing recombinant alkaline phosphatase, involves inoculating or
CC PT culturing Chinese hamster ovary cells in culture medium, isolating
CC PT phosphatase, performing additional protein purification step, and
CC PT subjecting to chromatography.
XX
CC PS Claim 48; SEQ ID NO 1; 85pp; English.
XX
CC The present invention relates to a novel method for producing recombinant
CC alkaline phosphatase. The method involves: (a) inoculating Chinese
CC hamster ovary (CHO) cells expressing recombinant alkaline phosphatase in
CC culture medium; (b) culturing the CHO cells in culture medium; (c)
CC isolating the recombinant alkaline phosphatase from the cell culture of
CC (c) by at least one purification step to form harvest clarified culture
CC fluid (HCCF) with a total sialic acid content (TSAC) of 2.1-4.3 mol/mol;
CC (d) performing at least one additional protein purification step to form
CC a filtration pool (UFDF), where the UFDF is held at a temperature of 13-
CC 27 degree C for 1-60 hours, and at a protein concentration of 1.7-5.3 g/l
CC ; and (e) subjecting the UFDF to at least one chromatography step to
CC obtain partially purified recombinant alkaline phosphatase, where the
CC recombinant alkaline phosphatase has a TSAC of 0.7-3.5 mol/mol. The
CC invention also provides: a method for using recombinant alkaline
CC phosphatase to increase cleavage of inorganic pyrophosphate (PPi) in a
CC subject; a method for controlling TSAC in a TSAC-containing recombinant
CC protein; a method for controlling glycosidase activity in mammalian cell
CC culture; and a method for treating a subject suffering from a condition
CC associated with alkaline phosphatase deficiency. The method is also
CC useful for treating diseases, preferably diseases having skeletal
CC manifestations, such as hypophosphatasia. The present sequence is a
CC fusion protein construct comprising a soluble catalytic domain of human
CC tissue non specific alkaline phosphatase (TNSALP) and a human
CC immunoglobulin G1 Fc domain a deca-aspartate peptide.
XX
SQ Sequence 726 AA;
ALIGNMENT:
Query Match 100.0%; Score 3886; Length 726;
Best Local Similarity 100.0%;
Matches 726; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 LVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFLGDGMGVSTVTAARILKGQL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 LVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFLGDGMGVSTVTAARILKGQL 60
Qy 61 HHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYLCGVKANEGTVGVSAATERS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 HHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYLCGVKANEGTVGVSAATERS 120
Qy 121 RCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSAAYAHSADRDWYSDNEMPPEAL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 RCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSAAYAHSADRDWYSDNEMPPEAL 180
Qy 181 SQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPKNKTDVEYESDEKARGTRLDGLDLVDTWK 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPKNKTDVEYESDEKARGTRLDGLDLVDTWK 240
Qy 241 SFKPRYKHSHFIWNRTELLTLDPHNVDYLLGLFEPGDMQYELNRNNVTDPSLSEMVVVAI 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 SFKPRYKHSHFIWNRTELLTLDPHNVDYLLGLFEPGDMQYELNRNNVTDPSLSEMVVVAI 300
Qy 301 QILRKNPKGFFLLVEGGRIDHGHHEGKAKQALHEAVEMDRAIGQAGSLTSSEDTLTVVTA 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 QILRKNPKGFFLLVEGGRIDHGHHEGKAKQALHEAVEMDRAIGQAGSLTSSEDTLTVVTA 360
Qy 361 DHSHVFTFGGYTPRGNSIFGLAPMLSDTDKKPFTAILYGNGPGYKVVGGERENVSMVDYA 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 DHSHVFTFGGYTPRGNSIFGLAPMLSDTDKKPFTAILYGNGPGYKVVGGERENVSMVDYA 420
Qy 421 HNNYQAQSAVPLRHETHGGEDVAVFSKGPMAHLLHGVHEQNYVPHVMAYAACIGANLGHC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 HNNYQAQSAVPLRHETHGGEDVAVFSKGPMAHLLHGVHEQNYVPHVMAYAACIGANLGHC 480
Qy 481 APASSLKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 APASSLKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 540
Qy 541 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE 600
Qy 601 KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT 660
Qy 661 TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKDIDDDD 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKDIDDDD 720
Qy 721 DDDDDD 726
||||||
Db 721 DDDDDD 726
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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over (a) claims 1-17, 21-22 of U.S. Patent No. 11, 913,039, and (b) claims 1-18 of U.S. Patent No. 11,352,612. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
Claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 of the instant application are directed in part to a method for producing a recombinant alkaline phosphatase, wherein said recombinant alkaline phosphatase has at least 90% sequence identity to the polypeptide of SEQ ID NO: 1, wherein said method comprises inoculating a bioreactor having a volume of at least 2 L to 20000 L with a CHO cell that expresses the recombinant alkaline phosphatase, obtaining an aqueous culture medium comprising the recombinant alkaline phosphatase, obtaining an aliquot from the aqueous culture medium to determine the total sialic content (TSAC) molar concentration per mole of the recombinant alkaline phosphatase in the aliquot, and harvesting the aqueous culture medium, wherein the determination of TSAC requires acid hydrolysis to release the TSAC, wherein the aliquot is centrifuged and the supernatant removed. Please note that the use of a chromatography column is optional. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
Claims 1-17, 21-22 of U.S. Patent No. 11, 913,039 are directed in part to a method of producing recombinant alkaline phosphatase comprising (a) inoculating Chinese Hamster Ovary (CHO) cells expressing recombinant alkaline phosphatase; (b) culturing the CHO cells in culture medium; (c) isolating the recombinant alkaline phosphatase from the culture medium by at least one purification step to form harvest clarified culture fluid (HCCF) with a total sialic acid content (TSAC) of about 2.1 mol/mol to about 4.3 mol/mol; and (d) performing at least one additional protein purification step, wherein the culturing step is performed in a bioreactor having a volume of 0.25 L to 25000 L, and wherein the recombinant alkaline phosphatase comprises SEQ ID NO: 1. SEQ ID NO: 1 of U.S. Patent No. 11, 913,039 is identical to SEQ ID NO: 1 of the instant application. Since the harvesting step requires a HCCF having a specific TSAC, it follows that the method of claims 1-17, 21-22 inherently requires taking a sample (aliquot) to measure TSAC of the harvest clarified culture fluid. The specification of U.S. Patent No. 11, 913,039 discloses purification of samples taken for TSAC determination with a protein A column and the use of acid hydrolysis for determination of TSAC as a preferred embodiment of the method by which TSAC is determined. The specification of U.S. Patent No. 11, 913,039 also discloses centrifugation as one of the preferred embodiments of the method by which the harvest clarified culture fluid is obtained. Therefore, the method of claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 of the instant application is either anticipated and/or render obvious by the method of claims 1-17, 21-22 of U.S. Patent No. 11, 913,039 in view of the preferred embodiments disclosed.
Claims 1-18 of U.S. Patent No. 11,352,612 are directed in part to a method for producing an asfotase alfa having the sequence of SEQ ID NO: 1, wherein said method comprises (i) providing a 100 L to 25,000 L fed-batch bioreactor comprising CHO cells capable of expressing the asfotase alfa having the sequence of SEQ ID NO: 1, and a culture medium suitable for conducting such expression, the culture medium comprising from about 25 μM to about 300 μM zinc; and (ii) culturing the cells under conditions suitable to express the recombinant polypeptides; wherein the pH of the culture medium is about 6.7 to about 7.1, wherein zinc is added into said culture medium such that the zinc concentration in the culture medium is maintained at a concentration of about 25 μM to about 300 μM of zinc, wherein the zinc is added into said culture medium in at least one bolus, continuously, or semi-continuously; wherein the asfotase alfa having the sequence of SEQ ID NO: 1 comprises a total sialic acid content (TSAC) between 0.9 to 3.5 mol sialic acid/mol protein monomer. SEQ ID NO: 1 of U.S. Patent No. 11,352,612 is identical to SEQ ID NO: 1 of the instant application. The specification of U.S. Patent No. 11,352,612 discloses a method as claimed wherein a sample is taken for TSAC determination at day 8, 9 and 10 of culturing (Figure 8) as a preferred embodiment of the method claimed. The specification of U.S. Patent No. 11,352,612 discloses a method as claimed wherein the medium comprising the polypeptide of SEQ ID NO: 1 is harvested, wherein cell debris is removed by centrifugation, the supernatant is recovered, and a sample of this supernatant is used for TSAC analysis. Therefore, the method of claims 1-3, 5-9, 14, 16, 18, 21, 24, 26, 28-29, 31, 36-38 of the instant application is either anticipated and/or render obvious by the method of claims 1-18 of U.S. Patent No. 11,352,612 in view of the preferred embodiments disclosed.
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
October 31, 2025
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