DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
The most recent claims are responsive to communications on 02/13/2026.
Claims 66-84 are pending.
Claims 78 is newly amended.
In regards to the species requirement, upon further consideration, the species election requirement for a kit comprising a plurality of purified protein variants corresponding to claims 81-84 is withdrawn.
Claims 66-77 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/27/2024.
Claims 78-84 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The prior rejection of claims 78-79 under 35 U.S.C. 102(a)(1) as being anticipated by Jung et al. (EP3101120A1, 2016, on IDS 11/16/2023, previously cited) are withdrawn in order to address the claims as amended and in order to address claims 81-84.
The prior rejection of claim 80 under 35 U.S.C. 103 as being unpatentable over Jung et al. (EP31011120A1, 2016, on IDS 11/16/2023, previously cited) in view of Salfeld et al. (US6090382A, 2000, previously cited) is withdrawn in order to address the claims as amended and in order to address claims 81-84.
The prior rejection of claims 78-80 under 35 U.S.C. 101 is withdrawn in order to address the claims as amended and in order to address claims 81-84.
Claim Interpretation
Claim 78 recites “wherein each of the homogenous purified proteins is isolated from a single cell culture.”
For disclosure of this feature, Applicant points to p2, first paragraph, which describes culturing “a population of cells”. Therefore, this has been interpreted as referring to a culture of a population of single cells, not a culture comprising a single cell.
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 78-84 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural product without significantly more.
Applicant is directed to the subject matter eligibility test for products processes (MPEP 2106; specifically, MPEP 2106(III) flowchart).
Briefly summarized here, the new guidance cites a two part test: is the claimed invention directed to a statutory class of invention (Step 1), if so then is the claimed invention as a whole directed to a law of nature, natural phenomena, or an abstract idea (i.e. set forth or described in the claim) (Step 2A, prong one), if so then is the claimed invention recite additional elements that integrate the judicial exception into a practical application (Step 2A, prong two), if not then does the claim as a whole amount to significantly more than the judicial exception (Step 2B).
Analysis on View of the Interim Guidance
In regards to Step 1, regarding claim 78, the claim is directed to a “plurality of homogenous purified protein variants” (i.e.) products, and thus a statutory class of invention (Step 1: YES).
In regards to Step 2A, prong one, claim 78 is drawn to “A plurality of homogeneous purified protein variants made by a method”, and is thus claim 78 is a product-by-process claim.
In regards to product-by-process claims MPEP 2113(I) states that while “The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979)”, and “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself”, “The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Thus, the question is whether the process steps impart structure on the product, but that patentability is based on the product itself.
In regards to Step 2A, prong one, specifically, for product-by-process claims, according to MPEP 2106.04(c)(I)(B), product-by-process claims are assessed by markedly different characteristics analysis (e.g., a claim to a cloned farm animal produced by a nuclear transfer cloning method, the analysis turned on whether the nature-based product in the claim has markedly different characteristics from its naturally occurring counterpart).
In the instant case, the product is plurality of homogeneous purified protein variants without more.
In regards to the process steps, step (a) requires culturing a population of cells in a culture medium in a vessel under a first condition to form a first variant preparation containing protein variant 1. Steps (b) and (c) require recovering and purifying the first protein variant 1, respectively. Step (d) requires measuring a target parameter, while step (e) requires culturing the cells under a second condition to forma second variant preparation comprising a protein variant 2 once a target parameter has been reached. Steps (f) and (g) require recovering and purifying the first protein variant 2, respectively.
In comparison to protein variants 1 and 2, the claim specifies that these proteins is an isolated from a single cell culture differ from each other by one or more of glycosylation, sialylation, charge, etc., as in claim 78.
However, as evidenced by Alzate et al. (Alzheimer’s Research and Therapy, 2014, previously cited), naturally occurring isoforms of the protein apolipoprotein E (ApoE), that vary in at least charge and isoelectric point (Title, Abstract, p1) are known to exist.
Additionally, as evidenced by Lechmann et al. (Biochemical and Biophysical Research Communications, 2005, previously cited), naturally occurring protein CD83 exists in both monomeric and dimerized forms (Title, Abstract, p132) and thus varies by dimerization.
Furthermore, as evidenced by Kommareddi et al. (Protein Journal, 2010, previously cited), naturally occurring isoforms of the protein CTL2/ SLC44A2, that vary in at least glycosylation and C-terminal sequence (Title, Abstract, p417; Fig. 1, p420) are known to exist.
This is confirmed by Damelang et al. (Frontiers in Immunology, 2024, previously cited), who evidences that naturally occurring immunoglobulin protein IgG can be divided into different subclasses (and thus protein variants) such as IgG1 (Introduction, p10) which can have different modifications such as glycosylation (Glycosylation, p07-08).
Therefore, the differences between proteins variants are differences found in naturally occurring proteins.
In regards to culturing steps, as evidenced by Marottoli et al. (Frontiers in Cell and Developmental Biology, 2021, previously cited), ApoE can be obtained from isolated brain endothelial cells in vitro (Title, Abstract, p1), while as evidenced by Huang et al. (Nat Protoc, 2013, previously cited), B cells isolated from peripheral blood can be cultured to produce IgG antibodies (Title, Abstract, p1).
In regards to purification (isolation) steps, and wherein each of the homogenous purified protein variants is isolated from a single cell culture, the purification of the proteins or that the fact that they are homogenous does not impart characteristics on the proteins themselves that are markedly different from those found in nature – they are only purified and homogenous, but structurally the same (see MPEP 2106.04(b), isolated DNA, of which codes proteins is a “product of nature” (see Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 580, 106 USPQ2d 1972, 1975 (2013); University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 758-59, 113 USPQ2d 1241, 1243 (Fed. Cir. 2014); see specifically, in Myriad, the Supreme Court made clear that not all changes in characteristics will rise to the level of a marked difference, e.g., the incidental changes resulting from isolation of a gene sequence are not enough to make the isolated gene markedly different. The claimed genes were otherwise structurally identical to the natural genes, e.g., they had the same genetic structure and nucleotide sequence as the BRCA genes in nature. The Supreme Court concluded that these isolated but otherwise unchanged genes were not eligible, because they were not different enough from what exists in nature to avoid improperly tying up the future use and study of the naturally occurring BRCA genes).
Therefore, the product-by-process steps do not appear to produce protein variants that are markedly different from naturally occurring protein.
As the Supreme Court made clear, neither naturally occurring compositions of matter, nor created compositions by a man-made process that are structurally identical to the naturally occurring compositions, are patent eligible. Thus, a synthetic, artificial, or non-naturally occurring product is not automatically eligible because it was created by human ingenuity or intervention. See, e.g., In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1337, 110 USPQ2d 1668, 1671-72 (Fed. Cir. 2014) (cloned sheep); cf. J.E.M. Ag Supply, Inc. v. Pioneer Hi-Bred Int’l, Inc., 534 U.S. 130-132, 60 USPQ2d 1868-69 (2001) (hybrid plant). Instead, the key to the eligibility of all non-naturally occurring products is whether they possess markedly different characteristics from any naturally occurring counterpart.
In regard to claims 79 and 80, which are directed to compositions comprising the purified protein variants, there is no indication in the specification that purification of said homogenous proteins results in the proteins having any characteristics (structural, functional, or otherwise) that are different from the naturally occurring proteins in their natural state. Because there is no difference between the claimed and naturally occurring proteins, the claimed proteins do not have markedly different characteristics, and thus are a “product of nature” exception.
In regards to claims 81-84, these claims are directed towards to composition as incorporated into a kit (this will be analyzed further under Step B as discussed below).
Accordingly, the claim is directed to an exception (Step 2A, prong one: YES).
With respect to Step 2A, prong two, limitations that may be enough to qualify as additional elements that integrate the judicial exception into a practical application include:
Improvements to another technology or technical field.
Improvements to the functioning of the computer itself.
Applying the judicial exception with, or by use of, a particular machine.
Effecting a transformation or reduction of a particular article to a different state or thing
Adding a specific limitation other than what is well-understood, routine and conventional in the field, or adding unconventional steps that confine the claim to a particular useful application.
Other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment.
With respect to Step 2A, prong two, limitations that were found not to be enough to qualify as additional elements that integrate the judicial exception into a practical application include:
Adding the words ‘‘apply it’’ (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, e.g., a claim to an abstract idea requiring no more than a generic computer to perform generic computer functions that are well understood, routine and conventional activities previously known to the industry
Adding insignificant extrasolution activity to the judicial exception, e.g., mere data gathering in conjunction with a law of nature or abstract idea
Generally linking the use of the judicial exception to a particular technological environment or field of use.
In regards to Step 2A, prong two, the instant claim does not recite additional elements or a combination of elements in the claims other than the natural product itself. While the claim recites process steps, as discussed above, the claim is drawn to a product, that the process steps are only considered in as much as they impart structure on the product, but that patentability is based on the product itself.
As discussed above, the differences between proteins variants are differences found in naturally occurring proteins and therefore, the product-by-process steps do not appear to produce protein variants that are markedly different from naturally occurring protein.
Moreover, again, as above, as evidenced by Marottoli or Huang, as cited above, culturing cells for obtaining proteins is well-understood and conventional in the art. Additionally, as evidenced by Brehcmann et al. (Biotechnology Progress, 2019, previously cited), methods for and Qian et al. (Blood, 1986, previously cited), methods for the purification of proteins such as IgG or erythropoietin (see Brehcmann, p1 and Qian, p258, respectively) are also well-understood and conventional in the art (therefore, Step 2A, prong two: NO).
In regards to Step 2B, the claim does not the claim recite additional elements that amount to significantly more than the judicial exception. In instant case, as above, the instant claim does not recite additional elements or a combination of elements in the claims other than the natural product itself. As discussed above, the differences between proteins variants are differences found in naturally occurring proteins and therefore, the product-by-process steps do not appear to produce protein variants that are markedly different from naturally occurring protein.
Additionally, while claims 79-80 incorporates the purified protein variants into a pharmaceutical composition, comprising a pharmaceutically acceptable dilutant, carrier, or excipient, Applicant’s disclosure provides no definition of a pharmaceutically acceptable dilutant, and amounts to no more than sterile water, which does not add significantly more to the naturally occurring cellular products.
In regards to claim 81-84, which incorporates the purified protein into a kit (and at varying levels of purity), according to MPEP 2106.04(c)(I)(A), where the claim is to a nature-based product in combination with non-nature based elements (e.g., a claim to “a yogurt starter kit comprising Lactobacillus in a container with instructions for culturing Lactobacillus with milk to produce yogurt”), the markedly different characteristics analysis should be applied only to the nature-based product limitation. For instance, for the yogurt starter kit example, the Lactobacillus would be analyzed for markedly different characteristics. The container and instructions would not be subject to the markedly different characteristics analysis as they are not nature-based products, but would be evaluated as additional elements in Prong Two (and Step 2B if needed) if it is determined that the Lactobacillus does not have markedly different characteristics from any naturally occurring counterpart and thus is a product of nature exception. See, e.g., Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280, 281 (1948) (although claims 7, 8, 13 and 14 recited an inoculant comprising a bacterial mixture and a powder base, only the bacterial mixture was analyzed).
As discussed above, the purified protein variants do not have markedly different characteristics from those found in nature.
Thus, turning to the kit (and containers), the analysis with whether the additional elements amount to an inventive concept (see flowchart MPEP 2106(III). However, placing the product of nature into a generic container such as a test tube does not add a meaningful limitation as it is merely a nominal or token extra-solution component of the claim, and is nothing more than an attempt to generally link the product of nature to a particular technological environment. Furthermore, as evidenced by Subramanian et al. (US20150110775A1, on IDS 11/16/2023), placing protein variants in kits was well-known in the art (paragraph [0411-0415]).
Therefore, claims 78-84 are directed to a natural cell product, that is not markedly different from its natural counterpart, is not integrated in a practical application, and does not include elements that amount to significantly more than the natural product itself and do not qualify as patent eligible subject matter under 35 U.S.C. § 101 (therefore, Step 2B: NO).
Claim Rejections - 35 USC § 102
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.
Claims 78-79 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jung et al. (EP3101120A1, 2016, on IDS 11/16/2023, previously cited).
Jung discloses a population (a plurality) of antibody (proteins) variants which vary (Abstract; claims 1, 8-9, and 27; Table 2; paragraphs [0001, 0012, 0025, 81-82]).
Jung discloses that the content of charge antibody isomers (charge variants) of monoclonal antibodies may vary according to the culture conditions of cell lines expressing the monoclonal antibodies (culture parameters, production media, etc.), and that the method has an advantage in that it can adjust the desired galactose content while simultaneously adjusting the content of the acidic antibody isomers to the desired range (paragraph [0073]; claim 27). Therefore, the plurality of protein variants as disclosed by Jung vary in terms of charge.
Jung discloses that the proteins are purified (paragraph [0027]).
Since purification results in the collection of proteins that are the same, they are deemed to also be homogenous.
In regards to the process steps, in regards to product-by-process claims MPEP 2113(I) states that while “The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979)”, and “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself”, “The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
As discussed above, Jung discloses the product as claimed.
The question then, is whether process steps impart distinctive structural characteristics to the final product.
As discussed above, Jung discloses that the proteins vary in terms of charge, which the process steps indicate is property indicative of a difference between variants.
Moreover, Jung discloses the process steps as well.
In regards to step (a), Jung discloses that cells (which a person of ordinary skill in the art would have recognized is a population of cells) were cultured in medium in a flask (a vessel) under a first condition (Final Osmolality) which formed a first protein variant (Acidic variants, day 1) (Table 2; paragraphs [0081-0082]).
In regards to step (b), a person of ordinary skill in the art would have recognized that measuring charge (Acidic variants) (Table 2; paragraphs [0045, 0081-0082]) would have necessarily required recovering the first variant preparation.
In regards to step (c), as above, Jung discloses that the proteins are purified (paragraph [0027]).
In regards to step (d), Jung discloses that an amount of parameter (time, day 1 of culture, i.e., duration of culture under the first condition) was measured (Table 2; paragraphs [0081-0082]).
In regards to step (e), Jung discloses that after that parameter was met (after day 1) the cells were cultured under a second condition (acidic variants) to form a second variant preparation comprising protein variant 2 (Acidic variants, day 2) (Table 2; paragraphs [0081-0082]).
In regards to step (f), as above, a person of ordinary skill in the art would have recognized that measuring charge (Acidic variants) (Table 2; paragraphs [0045, 0081-0082]) would have necessarily required recovering the first variant preparation.
In regards to step (g), as above, Jung discloses that the proteins are purified (paragraph [0027]).
Additionally, Jung only uses a (single) fed-batch culture (paragraph [0081-0082]; Fig. 2), and therefore, the protein variants are isolated from a single cell culture.
Therefore, in as much as the process steps could impart distinctive structural characteristics, the protein variants of Jung would have been expected to have these same structural characteristics.
In regards to claim 79, Jung discloses that the proteins may include all therapeutic antibodies, and may be adalimumab which is known in the art as a therapeutic agent (and thus, a pharmaceutical composition) for treating rheumatoid arthritis and Crohn’s disease (paragraph [0076]).
Therefore, Jung anticipates the invention as claimed.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 80 is rejected under 35 U.S.C. 103 as being unpatentable over Jung et al. (EP3101120A1, 2016, on IDS 11/16/2023, previously cited) in view of Salfeld et al. (US6090382A, 2000, previously cited).
Jung anticipates claims 78 and 79 as discussed above.
In regards to claim 80, Jung does not explicitly teach that the pharmaceutical composition (the antibodies) may also comprise a pharmaceutically acceptable carrier.
However, a person of ordinary skill in the art would have been motivated to incorporate the pharmaceutical composition into a pharmaceutically acceptable in order to effectively administer the pharmaceutical composition to patients. They would furthermore be motivated to incorporate the pharmaceutical composition into a pharmaceutically acceptable carrier because Salfeld teaches that pharmaceutically acceptable carriers can be used to control release of a particular pharmaceutical composition (Column 21, last paragraph). Furthermore, because Salfeld teaches that pharmaceutical compositions can be incorporated into pharmaceutically acceptable carriers (column 20, last paragraph) for administration to patients (column 22, top paragraph), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Jung and Salfeld render the invention unpatentable as claimed.
Claims 81-84 are rejected under 35 U.S.C. 103 as being unpatentable over Jung et al. (EP3101120A1, 2016, on IDS 11/16/2023, previously cited) in view of Subramanian et al. (US20150110775A1, on IDS 11/16/2023).
Jung anticipates claim 78 as discussed above.
In regards to claim 81, Jung does not explicitly teach that the plurality of protein variants are contained within a kit. However, it is long established that purified proteins (such as antibodies as taught by Jung) can be packaged as kits. For example, Subramanian teaches that antibody variants can be packaged as kits in containers (paragraphs [0407-0415]). A person of ordinary skill in the art would have been motivated to package the plurality of protein variants in a kit, for ease of distribution for administration in a clinical or research setting (paragraph [0407-0415]). Furthermore, because Subramanian teaches that protein (antibody) variants can be formulated in kits and Jung and Subramanian are in the same technical field of producing protein variants (antibodies), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 82, Subramanian teaches that the kit can comprise a container comprises at least one antibody (paragraph [0411]) and therefore, protein variants can be separately packaged into different containers. A person of ordinary skill in the art would have been motivated to package different protein variants into separate containers in order to provide a pure concentration of protein variant. Furthermore, because Subramanian teaches that containers can comprise a single antibody, it could have been done with predictable results and a reasonable expectation of success.
In regards to claims 83 and 84, as above, as above, Jung teaches that the proteins are purified (paragraph [0027]), and therefore, a container would comprise a protein variant that is at least 50% of that variant. Furthermore, a person of ordinary skill in the art would have been motivated to have a protein variant that is at least 50% of that variant in a container in order to provide purer concentration of that gradient. And again, because Jung teaches that a protein can be purified (which suggests 100% of a variant), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Jung and Subramanian render the invention unpatentable as claimed.
Response to Arguments
In regards to the rejections under 35 USC 101, Applicant argues that the claimed method is not drawn to a natural product (Remarks, p6). Specifically, in regards to Step 2A: Prong One, Applicant argues that the claimed plurality of homogenous protein variants contain protein variants have different characteristics as cited and that the claimed plurality of homogenous protein variants separated from each other would not be found in nature (Remarks, p6-7).
Applicant’s arguments filed 02/13/2026 have been fully considered but are not found persuasive.
As discussed above, in regards to Step 2A, prong one, claim 78 is drawn to “A plurality of homogeneous purified protein variants made by a method”, and is thus, claim 78 is a product-by-process claim.
In regards to product-by-process claims MPEP 2113(I) states that while “The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979)”, and “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself”, “The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Thus, the question is whether the process steps impart structure on the product, but that patentability is based on the product itself.
In regards to Step 2A, prong one, specifically, for product-by-process claims, according to MPEP 2106.04(c)(I)(B), product-by-process claims are assessed by markedly different characteristics analysis (e.g., a claim to a cloned farm animal produced by a nuclear transfer cloning method, the analysis turned on whether the nature-based product in the claim has markedly different characteristics from its naturally occurring counterpart).
In the instant case, the product is plurality of homogeneous purified protein variants without more.
In regards to the process steps, step (a) requires culturing a population of cells in a culture medium in a vessel under a first condition to form a first variant preparation containing protein variant 1. Steps (b) and (c) require recovering and purifying the first protein variant 1, respectively. Step (d) requires measuring a target parameter, while step (e) requires culturing the cells under a second condition to form a second variant preparation comprising a protein variant 2 once a target parameter has been reached. Steps (f) and (g) require recovering and purifying the first protein variant 2, respectively.
In comparison to protein variants 1 and 2, the claim specifies that these proteins are isolated from a single cell culture but differ from each other by one or more of sialylation, charge, etc., as in claim 78.
However, as evidenced by Alzate et al. (Alzheimer’s Research and Therapy, 2014, previously cited), naturally occurring isoforms of the protein apolipoprotein E (ApoE), that vary in at least charge and isoelectric point (Title, Abstract, p1) are known to exist.
Additionally, as evidenced by Lechmann et al. (Biochemical and Biophysical Research Communications, 2005, previously cited), naturally occurring protein CD83 exists in both monomeric and dimerized forms (Title, Abstract, p132) and thus varies by dimerization.
Furthermore, as evidenced by Kommareddi et al. (Protein Journal, 2010, previously cited), naturally occurring isoforms of the protein CTL2/ SLC44A2, that vary in at least glycosylation and C-terminal sequence (Title, Abstract, p417; Fig. 1, p420) are known to exist.
This is confirmed by Damelang et al. (Frontiers in Immunology, 2024, previously cited), who evidences that naturally occurring immunoglobulin protein IgG can be divided into different subclasses (and thus protein variants) such as IgG1 (Introduction, p10) which can have different modifications such as glycosylation (Glycosylation, p07-08).
Therefore, the differences between proteins variants are differences found in naturally occurring proteins.
In regards to culturing steps, as evidenced by Marottoli et al. (Frontiers in Cell and Developmental Biology, 2021, previously cited), ApoE can be obtained from isolated brain endothelial cells in vitro (Title, Abstract, p1), while as evidenced by Huang et al. (Nat Protoc, 2013, previously cited), B cells isolated from peripheral blood can be cultured to produce IgG antibodies (Title, Abstract, p1).
In regards to purification (isolation) steps, and wherein each of the homogenous purified protein variants is isolated from a single cell culture, the purification of the proteins or that the fact that they are homogenous does not impart characteristics on the proteins themselves that are markedly different from those found in nature – they are only purified and homogenous, but structurally the same (see MPEP 2106.04(b), isolated DNA, of which codes proteins is a “product of nature” (see Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 580, 106 USPQ2d 1972, 1975 (2013); University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 758-59, 113 USPQ2d 1241, 1243 (Fed. Cir. 2014); see specifically, in Myriad, the Supreme Court made clear that not all changes in characteristics will rise to the level of a marked difference, e.g., the incidental changes resulting from isolation of a gene sequence are not enough to make the isolated gene markedly different. The claimed genes were otherwise structurally identical to the natural genes, e.g., they had the same genetic structure and nucleotide sequence as the BRCA genes in nature. The Supreme Court concluded that these isolated but otherwise unchanged genes were not eligible, because they were not different enough from what exists in nature to avoid improperly tying up the future use and study of the naturally occurring BRCA genes).
Therefore, the product-by-process steps do not appear to produce protein variants that are markedly different from naturally occurring protein.
As the Supreme Court made clear, neither naturally occurring compositions of matter, nor created compositions by a man-made process that are structurally identical to the naturally occurring compositions, are patent eligible. Thus, a synthetic, artificial, or non-naturally occurring product is not automatically eligible because it was created by human ingenuity or intervention. See, e.g., In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1337, 110 USPQ2d 1668, 1671-72 (Fed. Cir. 2014) (cloned sheep); cf. J.E.M. Ag Supply, Inc. v. Pioneer Hi-Bred Int’l, Inc., 534 U.S. 130-132, 60 USPQ2d 1868-69 (2001) (hybrid plant). Instead, the key to the eligibility of all non-naturally occurring products is whether they possess markedly different characteristics from any naturally occurring counterpart.
In regard to claims 79 and 80, which are directed to compositions comprising the purified protein variants, there is no indication in the specification that purification of said homogenous proteins results in the proteins having any characteristics (structural, functional, or otherwise) that are different from the naturally occurring proteins in their natural state. Because there is no difference between the claimed and naturally occurring proteins, the claimed proteins do not have markedly different characteristics, and thus are a “product of nature” exception.
In regards to claims 81-84, these claims are directed towards to composition as incorporated into a kit (analyzed under Step B as discussed above).
Accordingly, the claim is directed to an exception (Step 2A, prong one: YES).
Additionally, Applicant argues that even if Step 2A: Prong Two were necessary, the claims recite additional elements that integrate the judicial exception into a practical application (Remarks, p7). Specifically, Applicant argues that the claimed product provides a technical solution to issues with currently used purification techniques, such as chromatography and filtration steps, that are not capable of purifying the product variants and obtaining a more homogeneous product (Remarks, p7). Continuing, Applicant argues that the specific method was discovered by Applicant to be optimal for preparation of homogenous protein variants having different characteristics (Remarks, p7).
Applicant’s arguments filed 02/13/2026 have been fully considered but are not found persuasive.
As discussed above, in regards to Step 2A, prong two, the instant claim does not recite additional elements or a combination of elements in the claims other than the natural product itself. While the claim recites process steps, as discussed above, the claim is drawn to a product, that the process steps are only considered in as much as they impart structure on the product, but that patentability is based on the product itself.
As discussed above, the differences between proteins variants are differences found in naturally occurring proteins and therefore, the product-by-process steps do not appear to produce protein variants that are markedly different from naturally occurring protein.
Moreover, again, as above, as evidenced by Marottoli or Huang, as cited above, culturing cells for obtaining proteins is well-understood and conventional in the art. Additionally, as evidenced by Brehcmann et al. (Biotechnology Progress, 2019), methods for and Qian et al. (Blood, 1986), methods for the purification of proteins such as IgG or erythropoietin (see Brehcmann, p1 and Qian, p258, respectively) are also well-understood and conventional in the art (therefore, Step 2A, prong two: NO).
In regards to Applicant’s argument that the claimed invention provides a technical solution over currently used filtration methods, is noted that the claims do not require specific filtration steps. Rather, the claim generically recites “purifying the protein . . . from the . . . variant preparation.”
Thus, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., specific filtration or purification steps) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Moreover, even if it did, the invention is drawn to a composition, not a method.
While the claim comprises product-by-process steps, as discussed above, according to MPEP 2113(I), while “The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979)”, and “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself”, “The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Therefore, even if the claim recited specific filtration steps, in order to have patentable weight they would have to impart distinctive structural characteristics to the final product.
Continuing, in regards to Step 2B, Applicant argues that the claims recite additional elements which amount to significantly more than the judicial exception (Remarks, p7). In particular, Applicant argues that the plurality of homogenous purified protein variants have different characteristics produced by a perfusion production culture method which allows for the production of multiple protein variants with optimized homogeneity (Remarks, p7). Continuing, Applicant argues that the additional elements of the perfusion production culture method avoid the requirement of the costly and time-consuming step of emptying a bioreactor or other manufacturing vessel in order to change culture media conditions (Remarks, 7-8).
Applicant’s arguments filed 02/13/2026 have been fully considered but are not found persuasive.
As discussed above, in regards to Step 2B, the claim does not the claim recite additional elements that amount to significantly more than the judicial exception. In instant case, as above, the instant claim does not recite additional elements or a combination of elements in the claims other than the natural product itself. As discussed above, the differences between proteins variants are differences found in naturally occurring proteins and therefore, the product-by-process steps do not appear to produce protein variants that are markedly different from naturally occurring protein.
Additionally, while claims 79-80 incorporates the purified protein variants into a pharmaceutical composition, comprising a pharmaceutically acceptable dilutant, carrier, or excipient, Applicant’s disclosure provides no definition of a pharmaceutically acceptable dilutant, and amounts to no more than sterile water, which does not add significantly more to the naturally occurring cellular products.
In regards to claim 81-84, which incorporates the purified protein into a kit (and at varying levels of purity), according to MPEP 2106.04(c)(I)(A), where the claim is to a nature-based product in combination with non-nature based elements (e.g., a claim to “a yogurt starter kit comprising Lactobacillus in a container with instructions for culturing Lactobacillus with milk to produce yogurt”), the markedly different characteristics analysis should be applied only to the nature-based product limitation. For instance, for the yogurt starter kit example, the Lactobacillus would be analyzed for markedly different characteristics. The container and instructions would not be subject to the markedly different characteristics analysis as they are not nature-based products, but would be evaluated as additional elements in Prong Two (and Step 2B if needed) if it is determined that the Lactobacillus does not have markedly different characteristics from any naturally occurring counterpart and thus is a product of nature exception. See, e.g., Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280, 281 (1948) (although claims 7, 8, 13 and 14 recited an inoculant comprising a bacterial mixture and a powder base, only the bacterial mixture was analyzed).
As discussed above, the purified protein variants do not have markedly different characteristics from those found in nature.
Thus, turning to the kit (and containers), the analysis with whether the additional elements amount to an inventive concept (see flowchart MPEP 2106(III). However, placing the product of nature into a generic container such as a test tube does not add a meaningful limitation as it is merely a nominal or token extra-solution component of the claim, and is nothing more than an attempt to generally link the product of nature to a particular technological environment. Furthermore, as evidenced by Subramanian et al. (US20150110775A1, on IDS 11/16/2023), placing protein variants in kits was well-known in the art (paragraph [0411-0415]).
Therefore, claims 78-84 are directed to a natural cell product, that is not markedly different from its natural counterpart, is not integrated in a practical application, and does not include elements that amount to significantly more than the natural product itself and do not qualify as patent eligible subject matter under 35 U.S.C. § 101 (therefore, Step 2B: NO).
In regards to the rejections under 35 USC 102, Applicant argues that Jung does not disclose the claims as amended (Remarks, p8).
Jung discloses a population (a plurality) of antibody (proteins) variants which vary (Abstract; claims 1, 8-9, and 27; Table 2; paragraphs [0001, 0012, 0025, 81-82]).
Jung discloses that the content of charge antibody isomers (charge variants) of monoclonal antibodies may vary according to the culture conditions of cell lines expressing the monoclonal antibodies (culture parameters, production media, etc.), and that the method has an advantage in that it can adjust the desired galactose content while simultaneously adjusting the content of the acidic antibody isomers to the desired range (paragraph [0073]; claim 27). Therefore, the plurality of protein variants as disclosed by Jung vary in terms of charge.
Jung discloses that the proteins are purified (paragraph [0027]).
Since purification results in the collection of proteins that are the same, they are deemed to also be homogenous.
In regards to the process steps, in regards to product-by-process claims MPEP 2113(I) states that while “The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979)”, and “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself”, “The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
As discussed above, Jung discloses the product as claimed.
The question then, is whether process steps impart distinctive structural characteristics to the final product.
As discussed above, Jung discloses that the proteins vary in terms of charge, which the process steps indicate is property indicative of a difference between variants.
Moreover, Jung discloses the process steps as well.
In regards to step (a), Jung discloses that cells (which a person of ordinary skill in the art would have recognized is a population of cells) were cultured in medium in a flask (a vessel) under a first condition (Final Osmolality) which formed a first protein variant (Acidic variants, day 1) (Table 2; paragraphs [0081-0082]).
In regards to step (b), a person of ordinary skill in the art would have recognized that measuring charge (Acidic variants) (Table 2; paragraphs [0045, 0081-0082]) would have necessarily required recovering the first variant preparation.
In regards to step (c), as above, Jung discloses that the proteins are purified (paragraph [0027]).
In regards to step (d), Jung discloses that an amount of parameter (time, day 1 of culture, i.e., duration of culture under the first condition) was measured (Table 2; paragraphs [0081-0082]).
In regards to step (e), Jung discloses that after that parameter was met (after day 1) the cells were cultured under a second condition (acidic variants) to form a second variant preparation comprising protein variant 2 (Acidic variants, day 2) (Table 2; paragraphs [0081-0082]).
In regards to step (f), as above, a person of ordinary skill in the art would have recognized that measuring charge (Acidic variants) (Table 2; paragraphs [0045, 0081-0082]) would have necessarily required recovering the first variant preparation.
In regards to step (g), as above, Jung discloses that the proteins are purified (paragraph [0027]).
Additionally, Jung only uses a (single) fed-batch culture (paragraph [0081-0082]; Fig. 2), and therefore, the protein variants are isolated from a single cell culture.
Therefore, in as much as the process steps could impart distinctive structural characteristics, the protein variants of Jung would have been expected to have these same structural characteristics.
In regards to the rejections under 35 USC 103, Applicant argues that Jung in view of Salfeld does not disclose the invention as claimed (Remarks, p9).
Applicant’s arguments filed 02/13/2026 have been fully considered but are not found persuasive. Jung anticipates the invention as discussed above.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Yang et al. (US2016/0304928A1).
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
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