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 .
Specification
The use of the term GlutaMAX, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology, capitalized wherever it appears, and, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1, 6, 8-13, 16, and 18-19 are objected to because of the following informalities:
Claims 1, 6, 11, 13, 16, and 18-19 should be corrected to say “concentration between” rather than “concentration of between” to be consistent with the terminology of the other claim limitations.
Claims 8, 11, and 16 should be corrected to say “percent volume between” rather than “percent volume of between”.
Claims 9, 14, and 15 should be corrected to say “a bioreactor” rather than “the bioreactor” because claim 1, from which claims 9 and 14 ultimately depend, does not comprise a bioreactor but rather includes a bioreactor in an intended use phrase.
Claim 10 should be corrected to say “plurality of medium components” rather than “plurality medium components”.
Claim 12 should be corrected say “about 0.68 mg/mL and 0.95 mg/mL”.
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 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.
Claims 1-19 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
The term “optimized” recited in claims 1, 3, and 9-10 is a relative term which renders the claims indefinite. Claims 2, 4-8, and 12-15 depend from claim 1, and claim 11 depends from claim 10, and thus inherit the relative term. The term “optimized” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification does not provide examples or definition for 1) the components of the medium that require optimization or 2) the degree or criteria of success to which a medium must be optimized for use in a bioreactor with partial medium exchanges. Therefore, the boundaries of medium formulation are not clearly delineated, rendering the claim indefinite as to the scope the claimed subject matter.
Claims 8, 11, and 16 recite the trademark GlutaMAX®. Claims 12-15 depend from claim 8 and claims 17-18 depend from claim 16 and thus inherit the trademark. Where 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 35 U.S.C. § 112(b). See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope cannot be ascertained since the trademark or trade name cannot be used properly to identify or describe any particular material or product. A trademark or trade name is used to identify a source of goods and not the goods themselves. In the present case, the trademark is used to identify or describe an L-alanyl-L-glutamine dipeptide and, accordingly, the identification and description is indefinite.
Claim 19 provides for the use of the medium comprising iron (III) citrate within a bioreactor, but, since the claim does not set forth any steps involved in the process of using of the medium, it is unclear what method or process applicant is intending to encompass. A claim is indefinite where it merely recites a use without any active, positive steps delimiting how this use is actually practiced. There are no active steps recited in the claim that clearly indicate how the medium is being used.
Claim Rejections - 35 U.S.C. § 112(d)
The following is a quotation of 35 U.S.C. § 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 13 is rejected under 35 U.S.C. § 112(d) for failing to further limit the subject matter of the claim upon which it depends. Claim 13 recites “iron (III) citrate at a concentration of between 1 μg/mL and 500 μg/mL”. Claim 13 ultimately depends from claim 1, which also recites “iron (III) citrate at a concentration of between 1 μg/mL and 500 μg/mL”, and therefore fails to limit the scope of claim 8. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 U.S.C. § 101
The following is a quotation of 35 U.S.C. § 101:
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.
Claim 10 is rejected under 35 U.S.C. § 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claim recites a medium optimized for in vitro bioreactor-based manufacture of red blood cells, which is not markedly different from its naturally occurring counterpart, blood plasma. The recitations “optimized for use in a bioreactor with periodic partial medium exchanges or additions” and “optimized for in vitro bioreactor-based manufacture of red blood cells” are statements of intended use. Statements reciting purpose or intended use may impose structural limitations; however, in the instant case it is unclear what structural limitations the recitations are intended to impart on the medium claimed, and therefore, is not given patentable weight. See MPEP § 2111.02. As noted by Yao (T. Yao and Y. Asayama. Rep Med Biol, 2016), media are formulated to mimic physiological conditions, and plasma itself may be used to cultivate cells (Sections 2.1 and 2.2). This judicial exception is not integrated into a practical application because the recitations “formulated for culturing cells”, “optimized for use in a bioreactor with periodic partial medium exchanges or additions”, and “optimized for in vitro bioreactor-based manufacture of red blood cells” do not impose meaningful structural limitations that distinguish the plurality of medium components from the composition of blood plasma. Claim 10 does not include additional elements sufficient to amount to significantly more than the judicial exception.
The Office published the guidance document entitled 2014 Interim Guidance on Patent Subject Matter Eligibility (Interim Eligibility Guidance), published December 16, 2014. Step 2A was revised to include two prongs (Federal Register / Vol. 84, No. 4 / Monday, January 7, 2019). Analysis is as follows:
Step 1: The claim is directed to a composition of matter (the medium). Step 1: Yes.
Step 2A, Prong One: Examiner evaluates whether the claim recites a judicial exception. The composition of matter (the medium) is directed to a product of nature exception. The claim recites a composition that is not markedly different from blood plasma. Step 2A, Prong One: Yes.
Step 2A, Prong Two: Examiner evaluates whether the claim recites additional elements that integrate the judicial exception into practical application of the exception. This exception is not integrated into practical application because the claim does not recite additional elements that integrate the judicial exception into practical application. The recitations “formulated for culturing cells”, “optimized for use in a bioreactor with periodic partial medium exchanges or additions”, and “optimized for in vitro bioreactor-based manufacture of red blood cells” merely link the use of the natural product to a particular technological environment or field of use, which is not indicative of integrating the natural product into practical application. See MPEP § 2106.05(h). Step 2A, Prong Two: No.
Step 2B: Examiner evaluates whether the claim recites additional elements that individually or in combination amount to significantly more than the judicial exception (i.e., whether the additional elements provide an inventive concept). The additional elements recited in the claim do not add an inventive step to add significantly more than generally link the judicial exception to a particular technological environment or field of use when considered alone or in combination. Step 2B: No.
The markedly different characteristics analysis performed in Step 2A, Prong One is a comparison of the nature-based product limitation to its naturally occurring counterpart in its natural state. Markedly different characteristics can be expressed as the product’s structure, function, and/or other properties. Product of nature exceptions include both naturally occurring products and non-naturally occurring products that lack markedly different characteristics from any naturally occurring counterpart. See MPEP § 2106.04(b)(II). If the claim recites a nature-based product limitation that does not exhibit markedly different characteristics, the claim is directed to a product of nature exception, and the claim will require further analysis to determine eligibility based on whether additional elements add significantly more to the exception. In accordance with this analysis, a medium, for example, is eligible when there is a resultant change in characteristics sufficient to show a marked difference from blood plasma. It is concluded here, that the claimed medium is no markedly different from its naturally occurring counterpart, blood plasma, as the claim does not recite structural limitations that distinguish the medium composition from the composition of blood plasma.
The Supreme Court has identified several considerations for determining whether a claim with additional elements amounts to significantly more than the judicial exception itself. Limitations that may qualify as significantly more when recited in a claim with a judicial exception 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; or other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment.
Limitations that were found not to be enough to qualify as significantly more when recited in a claim with a judicial exception include: adding the words ‘apply it’ (or an equivalent) with the judicial exception; 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; adding insignificant extra-solution activity to the judicial exception; or generally linking the use of the judicial exception to a particular technological environment or field of use.
In the instant case, the limitations of the claims do not impose limits on the scope of the claim such that the claimed medium is markedly different from a naturally occurring product. Accordingly, based on analysis of the claim as a whole, claim 10 does not recite additional elements adding significantly more than the judicial exception. Thus, claim 10 is rejected under 35 U.S.C. § 101 because the claimed invention is not directed to patent eligible subject matter.
Claim Rejections - 35 U.S.C. § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. § 102:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-5 and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kriegerbecková (K. Kriegerbecková, et al. Eur J Clin Chem Clin Biochem, 33, 791-798, 1995).
Kriegerbecková teaches media for culturing HeLa cells comprising 5 μM (1.24 μg/mL) or 500 μM (124 μg/mL) ferric citrate (iron (III) citrate) (Materials and Methods). Both media formulations of Kriegerbecková fall within, and therefore anticipate, the claimed range of 1 - 500 μg/mL ferric citrate of claims 1-5. Note that the recitation “optimized for use in a bioreactor with periodic partial medium exchanges” in claim 1 is a statement of intended use. Statements reciting purpose or intended use may impose structural limitations; however, in the instant case it is unclear what structural limitations the recitation is intended to impart on the medium claimed, and therefore, is not given patentable weight. See MPEP § 2111.02. The media formulations taught by Kriegerbecková may be used for the same purpose and thus meet the limitations of claim 1.
With regard to claim 2, Kriegerbecková, teaches that the ferric citrate-containing media do not contain transferrin (holo-transferrin) (Materials and Methods).
With regard to claims 3-5, Kriegerbecková teaches that the ferric citrate-containing media use RPMI 1640 medium as the base (Materials and Methods). The medium RPMI 1640 comprises 20 amino acids and 11 vitamins (G.E. Moore, et al. JAMA, 1967). Therefore, the media taught in Kriegerbecková meet the claim limitation, “comprising a plurality of components including amino acids and vitamins”. Note that the recitation “optimized for in vitro bioreactor-based manufacture of therapeutics” of claim 3 is a statement of intended use. Statements reciting purpose or intended use may impose structural limitations; however, in the instant case it is unclear what structural limitations the recitation is intended to impart on the medium claimed and therefore, is not given patentable weight. See MPEP § 2111.02. Additionally, narrowing of the claimed subject matter to therapeutics that are cellular in nature (claim 4) or to red blood cells (claim 5) does not impose further structural limitations on the medium of claim 3. The media formulations taught by Kriegerbecková may be used for the same purpose and thus meet the limitations of claims 3-5.
With regard to claim 10, the recitation “optimized for use in a bioreactor with periodic partial medium exchanges or additions, the medium comprising a plurality [of] medium components optimized for in vitro bioreactor-based manufacture of red blood cells (RBCs)” is a statement of intended use. Statements reciting purpose or intended use may impose structural limitations; however, in the instant case it is unclear what structural limitations the recitation is intended to impart on the medium claimed. See MPEP 2111.02. Therefore, the media formulations taught by Kriegerbecková meet the claim limitation “formulated for culturing cells” of claim 10.
Claim Rejections - 35 U.S.C. § 103
The following is a quotation of 35 U.S.C. § 103:
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:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 and 3-19 are rejected under 35 U.S.C. § 103.
Claims 1, 3-7, and 9-10 are rejected under 35 U.S.C. § 103 as being unpatentable over Glen (K.E. Glen, et al. Biochem Eng J, 2018, cited by applicant in IDS) in view of Rousseau (AU2022236557A1, 02 Nov 2022) and Kriegerbecková.
Glen teaches a medium comprising supplemented Iscove’s Modified Dulbecco’s Medium (IMDM) for in vitro bioreactor-based manufacture of red blood cells as a therapeutic product (claims 1, 3-7, and 9-10) (Abstract, Materials and Methods). The medium taught by Glen comprises amino acids (claims 3-7), vitamins (claims 3-7), and inorganic salts and glucose (claim 7) (Materials and Methods) (Table 1). Glen does not teach iron (III) citrate as a medium component (claims 1 and 3-7). Additionally, several medium components required by claims 6-7 differ from those taught by Glen and those claimed in the immediate application.
Several medium components required by claims 6-7 – L-asparagine, L-cystine, L-lysine, L-tyrosine disodium salt, calcium chloride dihydrate, and magnesium sulfate heptahydrate – are obvious variants of those taught by Glen (Materials and Methods) (highlighted in Table 1). Substitution of ionic compounds is obvious in view of the prior art as these species dissociate into their component ions in aqueous solution. As noted by Baltz (J.M. Baltz, Humana Press, 2012), “once the medium is made, all ions of a given species are essentially interchangeable, and it is only the total concentration of each type of ion that is important for the physiochemical properties of the medium” (Section 1.1, p. 62). Substitution of ionic compounds in media formulation is known in the prior art, and it is custom practice as a part of routine optimization of media components to use final ion concentrations in solution as the target for optimization.
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Concentrations of the medium components taught by Glen differ from those claimed. However, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See MPEP § 2144.05.
Rousseau teaches a medium comprising a ferric iron source, and the preferred embodiment comprises supplying ferric citrate to a bioreactor at a rate sufficient to maintain iron saturation of the iron carrier protein transferrin (claims 1, 3-7, and 9-10) (pp. 12-13). Rousseau teaches that supplementing media with ferric citrate is preferred because the addition and replacement of proteins, such as transferrin, in media makes production of red blood cells at industrial-scale production too expensive for medical application (p. 1). Thus, supply of ferric citrate via perfusion to maintain iron saturation of transferrin allows for lower transferrin use, and therefore reduced cost, when cultivating red blood cells in a bioreactor. Rousseau additionally teaches the culture method in a perfusion bioreactor in which the cells and/or media may be circulated and returned to the bioreactor (i.e., a recirculating loop, claim 9) (p. 6). Rousseau teaches that perfusion is beneficial to supply nutrients, such as ferric citrate, to concentrate cells to levels unattainable in batch culture, to filter out waste products, and to separate enucleated red blood cells (pp. 6-7, 13). Rousseau demonstrates improved cell yield and reduced transferrin usage when using perfusion compared to a batch fed bioreactor process (pp. 14-15).
Kriegerbecková teaches media comprising 5 μM (1.24 μg/mL) or 500 μM (124 μg/mL) ferric citrate (Materials and Methods). Both media formulations taught Kriegerbecková comprise ferric citrate within the range of 1 - 500 μg/mL as required by claims 1, 3-7, and 9-10.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the medium for in vitro bioreactor-based manufacture of red blood cells as taught by Glen with the media containing ferric citrate as taught by Rousseau and Kriegerbecková and the recirculating perfusion loop as taught by Rousseau to arrive at the claimed medium and bioreactor system. One would have been motivated to make the combination because Rousseau teaches the benefits of adding ferric citrate to media to reduce production costs when culturing cells at industrial-scale production and the benefits of perfusion in bioreactors to improve nutrient supply, concentration of cells, waste filtering, and separation of cell populations. One would have a reasonable expectation of success in making the combination because Kriegerbecková demonstrates that ferric citrate is sufficient to supply cells with iron when used without transferrin, Rousseau teaches that media supplemented with ferric citrate can maintain iron saturation of transferrin when culturing cells with high iron requirements, and Rousseau demonstrates improvements in perfusion culture over batch culture.
Claims 8 and 11-18 are rejected under 35 U.S.C. § 103 as unpatentable over Glen, Rousseau, and Kriegerbecková as applied to claims 1 and 3-7,9-10 above and in further view of Nims (R.W. Nims and J.W. Harbell, In Vitro Cell Dev Biol, 2017) and Yao (T. Yao and Y. Asayama. Rep Med Biol, 2016).
Glen, Rousseau, and Kriegerbecková teach media comprising ferric citrate, amino acids, vitamins, inorganic salts, and glucose as discussed in the rejection of claims 1 and 3-7 above. The medium taught by Glen additionally comprises buffers, pH indicators, serum, proteins, metabolites (claims 8 and 11-18), and iron-saturated holo-transferrin (claims 12 and 17) (Materials and Methods, Table 1) and use of the medium in a bioreactor (claim 14). Rousseau teaches a perfusion bioreactor (i.e., recirculating loop, claim 15). Glen does not teach heat inactivated AB serum or GlutaMAX® as required by claims 8, 11-14, and 16-18.
The medium taught by Glen includes AB serum (serum from an individual with AB-positive blood type), but it is not specified whether the AB serum was heat inactivated as required by claims 8 and 11-18 (Table 1). Heat inactivation of serum is common practice in the art to inactivate cytotoxic complement proteins and reduce contamination risk from viruses and mycoplasma bacteria (Nims, p. 684).
The medium taught by Glen uses L-glutamine rather than L-alanyl-L-glutamine as required by claims 8 and 11-18 (recited as GlutaMAX®) (Table 1). Yao teaches that glutamine is an essential amino acid for energy supply and nucleic acid and protein synthesis in cultured mammalian cells, but readily decomposes to ammonia, a toxic metabolite (Section 4.4). Yao additionally teaches that glutamine may be substituted for L-alanyl-L-glutamine, which is resistant to degradation (Section 4.4).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to modify the medium taught by Glen by heat inactivating the AB serum and substitute glutamine for L-alanyl-L-glutamine to arrive at medium of the claimed invention. One would have been motivated to make the modification because heat inactivation of serum inactivates cytotoxic proteins and reduces contamination risk as taught by Nims and because L-alanyl-L-glutamine is more stable in solution than glutamine. One would have a reasonable expectation of success in making the combination because these modifications are well established practices in the art for improving cell culture media with well documented success.
Claim 19 is rejected under 35 U.S.C. § 103 as being unpatentable over Kriegerbecková in view of Kundu (S. Kundu, et al., John Wiliey & Sons, Inc., 2011).
Kriegerbecková teaches media comprising 5 μM (1.24 μg/mL) or 500 μM (124 μg/mL) ferric citrate (Materials and Methods). Both media formulations taught Kriegerbecková comprise ferric citrate within the range of 1 - 500 μg/mL as required by claim 19. Note that the recitation “formulated for use in a bioreactor with periodic partial medium exchanges” is a statement of intended use. Statements reciting purpose or intended use may impose structural limitations; however, in the instant case it is unclear what structural limitations the recitation is intended to impart on the medium claimed, and therefore, is not given patentable weight. See MPEP § 2111.02. Kriegerbecková does not teach determination of average depletion rates for a plurality of factors nor formulation of the medium based on the average depletion rates.
Kundu teaches several parameters commonly used for measurement of cell culture growth and product formation, including specific nutrient consumption rate (i.e., average depletion rates for a plurality of factors, claim 19) (Table 3.1, p. 34). Kundu additionally teaches that “feed solutions may be added to the bioreactor to supply enough nutrients to the growing and productive cells according to a predetermined regimen” (i.e., formulating the medium based on the average depletion rates to supply the plurality of factors to allow for cell growth and proliferation while maintaining a homeostatic culture environment, claim 19) (p. 38). Kundu notes that these are “fundamental chemical engineering principles ... used in process and equipment design for biologics manufacturing” (p. 48).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the medium comprising ferric citrate as taught by Kriegerbecková with a method determination of average nutrient depletion rates and formulation of the medium based on average nutrient depletion rates as taught by Kundu to arrive at the claimed invention. One would have been motivated to make the combination because modifying the formulation of media and optimizing the formulation to promote cell growth and proliferation is considered routine in the operation of bioreactor systems. One would have a reasonable expectation of success in making the combination because calculation and utilization of parameters correlated to cell growth and proliferation are based on well-established and broadly used engineering principles that may be applied to any medium or bioreactor system, including those with ferric citrate and partial medium exchanges.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric B Wright whose telephone number is (571) 272-2607. The examiner can normally be reached Mo - Fr, 09:00 a.m. - 05:00 p.m. Eastern. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571) 272-4517.
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/Eric B Wright/Examiner, Art Unit 1632
/VALARIE E BERTOGLIO/ Primary Examiner, Art Unit 1632