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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 6/16/2025 has been entered.
Response to Amendment
The amendment filed 6/16/2025, amending claims 1, 5, and 6 is acknowledged. Claims 1-8, 10-17, 20, and 23 are pending and under examination. Applicant’s amendments to the claims have overcome each and every 112(b) rejection previously set forth in the Final Office Action mailed 2/18/2025.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The claims of the instant case are entitled to the priority date of EP19166531.4, filed 04/01/2019.
Claim Rejections - 35 USC § 112(a) – Written Description
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.
Claim 6 is 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 6 recites: “The method of claim 1, wherein the at least one feeding input that is adjusted in step e) is at least one feeding input selected from the group consisting of: O2 gassing rate, compressed air gassing rate, CO2 gassing rate, N2 gassing rate, input of feed solution, composition of feed solution, addition or omission of individual ingredients in feed solution, addition of protective agents, input of pH buffer, addition of components related to increased productivity or prevention of cell death, addition of proliferation stimulators, differentiation factors, and addition of specific inhibitors.”
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The claim is broad for describing the feeding input(s) (i.e., subgenera) in terms of functional language, and at a high level of generality. For example, the recitation of “addition or omission of individual ingredients in feed solution” encompasses a vast genera of “ingredients” and possible method steps (i.e., structures). The specification does not provide any further guidance on what this recitation encompasses, as a search of “ingredients” in the instant specification only returned the claim language. Additionally, the specification does not further define the metes and bounds of a “feed solution”. As written, it is unclear how adjusting the “composition of feed solution” differs structurally from “addition or omission of individual ingredients in feed solution”, for example.
Further, the specification does not provide an ordinary artisan enough guidance to determine what feeding input(s) are “proliferation stimulators”, “specific inhibitors”, or protective agents”, for example (i.e., what is the structure of these feeding inputs, as terms such as “proliferation stimulators” only speak to the function of the feeding input).
The recited subgenera of claim 6 merely state functional characteristics about the claimed feeding input(s) without providing any indication about how the functional characteristic is provided. The specification fails to disclose what structural components of a “feeding input” is necessary and sufficient to cause the recited functional properties, and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
The claims fail to recite, and the specification fails to disclose, the structure/function nexus between the genus of feeding input(s) adjusted in step e) [structure] and the resulting functional properties of the feeding input(s) such as “addition of components related to increased productivity or prevention of cell death”.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 112(b)
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 4, 6, 8, and 16 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 4 recites the broad recitation “a cell-based product”, and the claim also recites “biomolecule” which is the narrower statement of the range/limitation. A biomolecule is necessarily produced from a cell. Page 16 of the specific recites “according to further embodiments of the invention, the biomolecule is a recombinant biomolecule, preferably selected from the group consisting of an antibody, or fragment or derivative thereof, or an antibody mimetic, and/or a growth factor, hormone or cytokine”. Each of these examples recited in the specification may be considered “a cell-based product”.
Claim 6 recites the broad recitations “individual ingredients in feed solution” and “components related to increased productivity or prevention of cell dell”, and the claim also recites “protective agents”, “proliferation stimulators”, “differentiation factors”, and “specific inhibitors” which are the narrower statements of the range/limitation.
Claim 8 recites the broad recitation “O2 consumption”, and the claim also recites “dissolved oxygen” which is the narrower statement of the range/limitation. O2 consumption necessarily measures dissolved oxygen. Claim 8 also recites the broad recitation of “pCO2” (partial pressure dissolved CO2), and also recites “pH”. PCO2 is a pH indicator, as high CO2=acidic pH, and low CO2 = basic pH. The claim also recites “metabolite levels” (e.g., ions such as NaCl, glucose, urea, etc.) and “osmolality” and “osmolarity”, which measure metabolite molecule levels. It is also unclear how “osmolality” and “osmolarity” differ, as the specification uses them interchangeably (e.g., see pg. 15). Further, claim 8 recites the broad recitation “trypan blue staining”, and the claim also recites “cell permittivity” which is the narrower statement of the range/limitation. Trypan blue is a cell permittivity dye (i.e., dead cells stain with the dye).
Claim 16 recites the broad recitation “organic acid or amino acid”, and the claim also recites “lactate” and “acetate” which is the narrower statement of the range/limitation. Lactate and acetate are organic acids.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Interpretation
Claim 1 recites “determining a soft sensor parameter based on at least one system and/or product parameter”. This recitation encompasses contemplating (i.e., determining) another parameter that step e) may be based upon, but does not require the integration of the soft sensor into the method (i.e., the parameter of step e) may be adjusted based on contemplating a soft sensor parameter to be used in the method, but is not required to be adjusted in response to a soft sensor parameter reading, output, etc.).
Amending claim 1 to add “wherein the soft sensor is used as a basis for the adaptation in step e)” does not change the interpretation of recitation above, as step d) already recites “in response to the outcome of step d)”, which reads are the determination of the soft sensor being used to adjust in step e). The new addition of “wherein the soft sensor is used as a basis for the adaptation in step e)” still does not require the integration of the soft sensor into the method, nor does it state how the soft sensor is used (i.e., does not further limit the structure of the claimed invention).
Claim Rejections - 35 USC § 102- Maintained
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-8, 10-17, 20, and 23 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Huacells (US 20190352589 A1, filed 12/21/2018).
Regarding claim 1, Huacells discloses
A method for a cell cultivation system, wherein the cultivation system comprises two or more cultivation vessels (i.e., hollow tube cartridges) [0089] for the production of at least one biologic agent and/or cell, wherein the cultivation vessels comprise cells in a suitable cultivation medium (Abstract), the method comprising the steps of
taking two or more liquid samples (i.e., cells, cell media, etc.) from two or more cultivation vessels (Example 1, beginning [0151], specifically taking Jurkat cells cultured in two, differently sized hollow fiber cartridges)
optionally, purifying the two or more liquid samples,
analyzing at least one of the two or more liquid samples to acquire data relating to at least
one system parameter indicative for at least one of nutrient status and/or medium quality of the cultivation medium, or cell density, or cell viability and/or
one product parameter indicative for biologic agent quality and/or cell quality, (i.e., glucose and lactate levels) [0151-0152]
d) determining a soft sensor parameter based on at least one such system parameter and/or product parameter (i.e., glucose uptake and lactate secretion), wherein the soft sensor is used as a basis for the adaptation in step e) [0082 – “the computing system of the automated cell culture system for monitoring glucose consumption and lactate production in the cell culture media, e.g., as an indication of cell growth.”; 0087 – “one or more of the detected parameters can be used by the computing system to determine a phase of the cell culturing, e.g., an initial, slow growth phase, in a rapid (e.g., exponential) growth phase, or in a plateau in which cell proliferation is reduced or ceases. For instance, the glucose or lactate levels in the cell culture media, the dissolved oxygen concentration in the cell culture media, the rate at which the amount of nutrients in the cell culture media in the fluidic circuit decreases, or other parameters can be indicative of the phase of the cell culturing”] [0012; 0016; 0073; 0134], and
e) in response to the outcome of step d), adjusting, in real-time, at least one process parameter and/or at least one feeding input in at least one cultivation vessel of the present cultivation system, or of a subsequent cultivation system (e.g., “The conditions of the cell culture environment in the automated cell culture system can be dynamically and automatically adjusted responsive to real time sensor monitoring to maintain steady state conditions in the cell culture media, e.g., to maintain parameters” [0065]; “For instance, components of the automated cell culture system can be controlled in real time responsive to changes in parameters of the cell culturing environment, e.g., without waiting for a user to manually operate the system or manually input control instructions. The real time control of the system responsive to real time monitoring enables target parameters to be consistently maintained” [0069]) [0070; 0076].
Regarding claim 2, Huacells discloses the cell cultivation system being a bioreactor system suitable for culturing cells, wherein the bioreactor system comprises two or more bioreactors (i.e., hollow fiber cartridges of cell culture reactors) [0151; 0155].
Regarding claim 3, Huacells discloses the method of claim 1, further comprising transferring at least one of the two or more liquid samples from the cell cultivation system to an array of reaction vessels, wherein the array of reaction vessels comprises at least one of a microtitre plate with two or more wells, a series of sample cups or sample vials, or an array of microreaction tubes [0090-0091] (i.e., tubes, also known as capillaries, of the hollow tube cartridge; cell culturing reagents can pass from the intra-capillary space to the extra-capillary space).
Regarding claim 4, Huacells discloses the method of claim 1, wherein the biologic agent is selected from the group consisting of a biomolecule, a cell-based product (i.e., a cell), and a vaccine (e.g., Jurkat cells, human T lymphocytes) [0151; 0155, 0157].
Regarding claim 5, Huacells discloses the method of claim 1, wherein the process parameter that is adjusted in step d) is at least one of the process parameters selected from the group consisting of: a cultivation temperature set point, stirring speed, stirrer blade tip speed, pH set-point, DO set-point, viable cell density set-point, conductivity, osmolality, specific power input, and bubble size [0065; 0069-0070].
Regarding claim 6, Huacells discloses the method of claim 1, wherein the at least one feeding input that is adjusted in step d) is at least one feeding input selected from the group consisting of: gassing rate, compressed air gassing rate, CO2 gassing rate, N2 gassing rate, input of feed solution, composition of feed solution, addition or omission of individual ingredients in feed solution, addition of protective agents, input of pH buffer, addition of components related to increased productivity or prevention of cell death, addition of proliferation stimulators, differentiation factors, and addition of specific inhibitors [0065; 0069-0070].
Regarding claim 7, Huacells discloses the method of claim 1, wherein at least one further system parameter is measured on-line in at least one of the cultivation vessels (i.e., temperature of culture vessel measured) [0118].
Regarding claim 8, Huacells discloses the method of claim 7, wherein said further system parameter measured on-line is at least one system parameter selected from the group consisting of dissolved oxygen, pH, trypan blue staining, pC02, optical density, osmolality, osmolarity, cell permittivity, radio-frequency (RF) impedance, cultivation time, exhaust gas composition, O2 consumption, temperature, stirrer speed, and metabolite levels [0118].
Regarding claim 10, Huacells discloses the method of claim 1, wherein the two or more liquid samples are taken with at least one of a robotic liquid handler and/or a multi-valve sample system [0090-0091] (i.e., tubes, also known as capillaries, of the hollow tube cartridge; cell culturing reagents can pass from the intra-capillary space to the extra-capillary space) [0075; 0099; 0101] (i.e., valves to pump cell culture media).
Regarding claims 11 and 12, Huacells discloses the method of claim 10, wherein taking of two or more liquid samples is triggered by a given system parameter (claim 11) [0110; 0124-0125] or is triggered by a timer (claim 12) [0106; 0110].
Regarding claim 13, Huacells discloses the method of claim 1, wherein at least one of the two or more liquid samples comprises supernatant from one of the cultivation vessels (i.e., supernatant is used to measure the lactate secretion of cells) [0154].
Regarding claims 14 and 15, Huacells discloses method of claim 1, wherein the system parameter indicative for cell density (claim 14) and/or cell viability (claim 15) is at least one system parameter selected from the group consisting of: optical density [0134], cell permittivity, radio-frequency (RF) impedance, transmission spectrum, light scattering, and trvpan blue staining (Huacells used the Countess FL II cell counter to measure cell density and viability, which uses brightfield and two optional fluorescent channels with optics and image analysis, along with standard trypan blue) – see www.thermofisher.com/us/en/home/references/newsletters-and-journals/bioprobes-journal-of-cell-biology-applications/bioprobes-70/countess-ii-fl-automated-cell-counter.html.)
Regarding claim 16, Huacells discloses method of claim 1, wherein the system parameter indicative for nutrient status and/or medium quality of the cultivation medium is at least one system parameter selected from the group consisting of glucose concentration, concentration of at least one trace element, vitamin, organic acid or amino acid, osmolality, osmolarity, lactate concentration, acetate concentration, ammonia concentration, and pH value [0087; 0151-0154].
Regarding claim 17, Huacells discloses method of claim 4, wherein the biomolecule is an antibody or fragment or derivative thereof, an antibody mimetic, a growth factor, a hormone or a cytokine [0065].
Regarding claim 20, Huacells discloses method of claim 1, wherein the product parameter indicative for quality of the cell-based product is at least one selected from the group consisting of presence of one or more given surface markers and cell viability (i.e., antibodies targeting CD3, CD4, and CD9 for T lymphocytes) [0158; 0160-0161.
Regarding claim 23, Huacells discloses method of claim 1, wherein the purification step comprises at least one step selected from the group consisting of protein A based purification, protein G based purification, affinity tag based purification, lectin based purification, ion chromatography, affinity chromatography, and size exclusion chromatography (i.e., Dynabeads CD3/CD28, which are magnetic beads coated with antibodies against CD3 and CD28, are a form of affinity chromatography and can also activated T cells) [0158; 0160].
Response to Arguments
Applicant's arguments filed 06/16/2025 have been fully considered but they are not persuasive.
The Applicant argues that step d) “involves the computation of a soft sensor parameter, which refers to a derived value computed via modeling or inference from data acquired from analyzed samples. This feature is distinct from a physical or directly measured parameter.
The soft sensor output as claimed is then used to control the cultivation process by adjusting at least one process parameter and/or feed input (step e)).
In contrast, paragraphs [0151] to [0154] of Huacells describe an automated cell culture system equipped with direct physical sensors for detecting environmental conditions such as pH, dissolved oxygen, and temperature. More precisely, in the described system Jurkat cells are cultured, and during the process fetal bovine serum and antibiotics were circulated in the fluidic circuit and glucose and lactate levels were monitored and calculated.
Furthermore, cell number and viability were measured Acridine Orange/Peroxide Iodide staining and an automated cell counter were used to measure cell number and viability.
However, all these measurements are direct, obtained from embedded or integrated sensors.
There is no computation or modeling of a soft sensor parameter according to present invention, nor is it suggested to use such soft sensor parameter for process control decisions.
Thus, the system in Huacells is limited to closed-loop feedback control based on physical sensor outputs, without involving computational modeling, data analytics, or soft sensor parameters.”
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., the claimed invention involves the computation of a soft sensor parameter) are not recited in the rejected claim(s). For example, the claim language does not require “computational modeling”. 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).
Page 13 of the instant specification recites :
“The term "soft sensor" as used herein, often also called "virtual sensor", describes a software or algorithm in which where several measurements are processed together, to obtain an integrated or processed output value that is then evaluated similar to a hardware sensor output. In cell culture applications, soft sensors are being used for a different purposes, as e.g., discussed in Ohadi et al (2015), Ohadi et al (2014),GustavssonR(2018), Abu-Absi at al (2011), Kroll et al (2017), or Luttmann et al (2012), the content of each of which is incorporated by reference herein. Some typical such soft sensors are shown in the following table:
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522
687
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Greyscale
In view of the guidance provided by the specification, Huacells does disclose a “soft sensor”. Some examples include:
[0012] “The automated cell culture system includes a gas source fluidically coupled to the interior of the housing; and a gas flow control device coupled to the gas source. The computing device is configured to control operation of the gas flow control device based on one or more of the detected parameters”
[0016] “The computing device is configured to determine the phase of the cell culture based on one or more of (i) one or more of the detected parameters and (ii) a history of one or more of the detected parameters.”
[0073] “The information [identifying or characterizing the cells to be cultured in the automated cell culture system] can be stored in a centralized data storage, such as cloud-based data storage, or in a distributed data storage system. The information can be analyzed, e.g., to the improve system performance, to tailor parameter threshold settings, or for other objectives. For instance, using the collected information, an artificial intelligence based cell culture algorithm can be developed or updated and applied to the automated cell culture system.”
[0134] “In some examples, operation of the rotational mount can be controlled by the computing device that controls the cell culture system. For instance, the rotational mount can be controlled to rotate the culture vessel by a prescribed amount on a prescribed schedule. In some examples, the rotation can be triggered by a sensed characteristic of the cells in the culture vessel. The sensed characteristic can include a density of cells in the culture vessel, a consumption rate of glucose, an accumulation of lactate, an index that is based on a combination of characteristics such as the consumption rate of glucose and the accumulation of lactate, or another sensed characteristic. For instance, an optical sensor, such as a still or video camera, can capture images of an interior of the culture vessel, and image analysis can indicate a density of cells in the culture vessel. When the density of cells reaches a threshold density, rotation can be triggered.”
Huacells discloses numerous examples of computing or modeling a soft sensor parameter, and using such a soft sensor for process control decisions.
Even if Huacells may not teach “data analytics” or “soft sensors” ipis verbis, they do disclose numerous examples of how an algorithm is being used to analyze data, and multiple measurements/parameters being processed together to obtain a processed value that is evaluated (i.e., a soft sensor).
Conclusion
No claims are allowed.
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/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638