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 .
Claim Status
Claims 1, 3, 5-7, 11, 16-21, 23, 27, 29, 33, 43, and 47 are pending.
Claims 1, 3, 5-7, 11, 16-21, 23, 27, 29, 33, 43, and 47are under examination.
Election/Restrictions
Applicant’s election without traverse of the following invention
Invention
Group I, claims 1, 3, 5-7, 11, 16-21, 23, 27, 29, 33, 43, and 47, drawn to a method of producing exosomes from mesenchymal stromal cells (MSCs), comprising the steps of: (a) culturing MSCs in the presence of an effective amount of interferon (IFN)y, tumor necrosis factor (TNF)oc, interleukin (IL)-1 b, and IL-17; and (b) collecting the exosomes from the culture in the reply filed on 2nd, December, 2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Claim Objections
Claims 1,7 and 18 are objected to because of the following informalities:
Claim 1 recites “tumor necrosis factor (TNF)oc” which appears to be a typographical error intended to be just “tumor necrosis factor (TNF)α.” Similarly, claim 7 recites “TNFoc” which appears to be a typographical error for “TNFα.”
Claim 18 recites “wherein system is configured” which is missing an article. It is recommended that Applicant amend to include an article in between “wherein” and “system.”
Appropriate correction is required.
Claim Interpretation
35 U.S.C. 112(f)
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
In the instant case, claim 18 is being interpreted under 35 U.S.C. 112(f) for the following reasons:
Regarding (A), the claim limitation uses a term used as a substitute for “means” (configured to) that is a generic placeholder for performing the claimed function (comprise continuous perfusion of medium through at least part of the system).
Regarding (B), the generic placeholder is modified by functional language (configured to).
Regarding (C) the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Therefore, regarding claim 18, the phrase “is configured to comprise continuous perfusion of medium through at least part of the system ” is interpreted as a means-function limitation under 35. U.S.C. 112f because it contains the generic placeholder “configured” that is modified by the functional language “to” and is not modified by sufficient structure, material, or acts for performing the claimed function because there are no other elements recited in the claim.
In the instant case, claim 21 is being interpreted under 35 U.S.C. 112(f) for the following reasons:
Regarding (A), the claim limitation uses a term used as a substitute for “means” (modified to) that is a generic placeholder for performing the claimed function (allow adherence of cells).
Regarding (B), the generic placeholder is modified by functional language (modified to).
Regarding (C) the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Therefore, regarding claim 21, the phrase “modified to allow adherence of cells” is interpreted as a means-function limitation under 35. U.S.C. 112f because it contains the generic placeholder “modified” that is modified by the functional language “to” and is not modified by sufficient structure, material, or acts for performing the claimed function because there are no other elements recited in the claim.
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 18, 21 and 29 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.
I am on the fence about making this rejection. Not sure it is indefinite. Claim 6 definitely speaks to the breadth of claim 1.
Regarding claim 18, the claim limitation “system is configured to comprise continuous perfusion of medium through at least part of the system” has been evaluated under the three-prong test set forth in MPEP § 2181, subsection I, but the result is inconclusive. Thus, it is unclear whether this limitation should be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because although the three prong test is met (see claim interpretation under 35 U.S.C. 112(f) above and MPEP § 2181, subsection I), the instant specification does not clearly set forth the corresponding structure for the means-function language. Therefore, the metes and bounds of the claims are unclear.
The boundaries of this claim limitation are ambiguous; therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Regarding claim 21, the claim limitation “modified to allow adherence of cells” has been evaluated under the three-prong test set forth in MPEP § 2181, subsection I, but the result is inconclusive. Thus, it is unclear whether this limitation should be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because although the three prong test is met (see claim interpretation under 35 U.S.C. 112(f) above and MPEP § 2181, subsection I), the instant specification does not clearly set forth the corresponding structure for the means-function language. It is noted that the instant specification recites “One or more surfaces inside a bioreactor may be modified to allow adherence of cells, including one or more surfaces inside the bioreactor being modified to comprise one or more extracellular matrix proteins, including at least fibronectin, for example” (para. [0010]). This does not clearly set forth the corresponding structure for the means-function language because it is listed as an example and therefore it is unclear whether the scope of the “modified to allow adherence of cells” encompasses other structure embodiments, and what those embodiments are.
Therefore, the metes and bounds of the claims are unclear.
The boundaries of these claim limitations are ambiguous; therefore, the claims are indefinite and are rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
In response to these rejections for claims 18 and 21, applicant must clarify whether this limitation should be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. Mere assertion regarding applicant’s intent to invoke or not invoke 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph is insufficient. Applicant may:
(a) Amend the claim to clearly invoke 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, by reciting “means” or a generic placeholder for means, or by reciting “step.” The “means,” generic placeholder, or “step” must be modified by functional language, and must not be modified by sufficient structure, material, or acts for performing the claimed function;
(b) Present a sufficient showing that 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, should apply because the claim limitation recites a function to be performed and does not recite sufficient structure, material, or acts to perform that function;
(c) Amend the claim to clearly avoid invoking 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, by deleting the function or by reciting sufficient structure, material or acts to perform the recited function; or
(d) Present a sufficient showing that 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, does not apply because the limitation does not recite a function or does recite a function along with sufficient structure, material or acts to perform that function.
Claim 29 contains the trademark/trade name “MEM”. 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) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe culture media components and, accordingly, the identification/description is indefinite.
Because these reagents were developed by the manufacturer at the time of the applicant’s invention under the trade name “MEM” and as a result is proprietary, which means what constitutes as “MEM” can change, and these changes do not need to be disclosed by these companies to the public. Accordingly, the identification of the trade name is indefinite and the applicant is advised to employ a sequence, the SeqID, IUPAC name and/or CAS number for this agent.
MPEP 2173.05(u) states that if a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). See also Eli Lilly & Co. v. Apotex, Inc., 837 Fed. Appx. 780, 784-85, 2020 USPQ2d 11531 (Fed. Cir. 2020).
Regarding the status of MEM as a trademark, Applicant is directed to MPEP 608.01(v) which defines a trademark as follows:
The term "trademark" includes any word, name, symbol, or device, or any combination thereof-
(1) used by a person, or
(2) which a person has a bona fide intention to use in commerce and applies to register on the principal register established by this chapter,
to identify and distinguish his or her goods, including a unique product, from those manufactured or sold by others and to indicate the source of the goods, even if that source is unknown.
Although the Trademark for MEM (98618995) was abandoned, it still meets the definition of a trademark according to the MPEP because it is a term “which a person has a bona fide intention to use in commerce” “to identify and distinguish his or her goods.” Since the trademark Application was filed (i.e. “applies to register on the principal register” MPEP 608.01(v) above), it falls under the definition of a trademark, even if the Trademark Status is now Dead/Abandoned.
Accordingly, for the reasons stated above, the claims are indefinite due to the presence of the trademark term “MEM.”
Generally, when the claims are indefinite, vague or unclear, they cannot be construed without speculation or conjecture; therefore, the indefinite claims are not treated on the merits with respect to prior art. See In re Steele, 305 F.2d 859, 862 (CCPA 1962) (A prior art rejection cannot be sustained if the hypothetical person of ordinary skill in the art would have to make speculative assumptions concerning the meaning of claim language.); see also In re Wilson, 424 F.2d 1382, 1385 (CCPA 1970) ("If no reasonably definite meaning can be ascribed to certain terms in the claim, the subject matter does not become obvious-the claim becomes indefinite."). Notwithstanding Steele, the Office has made every attempt to construe the claims in what the Office believes is the intent of the Applicants in the interest of compact prosecution.
Claim Rejections - 35 USC § 102/103
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.
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.
Claims 1, 3, 5-7, 11, 16-21, 23, 27, 29 and 43 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Anderson et al. (WO-2018/226758-A2; henceforth “Anderson”).
Regarding claim 1, Anderson discloses a method of producing exosomes ( “methods for purifying the cell-derived vesicles” abstract and “the cell-derived vesicles can comprise exosomes” para. [0008] and claim 1) from mesenchymal stromal cells (MSCs) (para. [0004-0005, 0046-0051, 0054, 0056, 0059, 0067-0074, 0086-0087, 0089, 0136, 0203-0204, 0206]; Example 1Table 1comprising the steps of:
culturing MSCs in the presence of an effective amount of interferon (IFN)y, tumor necrosis factor (TNF)α, interleukin (IL)-1 b, and IL-17 (see “the stem cells are cultured in the presence of one or more agents selected from an inflammatory agent” and “the inflammatory agent is selected from tumor necrosis factor alpha ("TNFα"), interleukin 6 ("IL -6"), interleukin 17 ("IL-17"), interleukin 1 ~ ("IL-1 β), interferon gamma ("IFNy")” parra. [0008, 0021] and “In some embodiments, stimulation is achieved with one or more inflammatory agents” para. [0129] and Table 1 for inflammatory agents; see para. [0012, 0036] for effective amounts )
collecting the exosomes from the culture (see “concentrating the cell-derived vesicle containing fraction to provide a purified population of cell-derived vesicles” para. [0143]; abstract; claim 158, 163; “vesicle isolation” para. [0127, 0129, 0134, 0136, 0187, 0191-0194, 0200]; see in particular “Isolation of Extracellular Vesicles” para. [0142-0154] “Vesicle isolation and characterization” para. [0208] and Example 1).
Regarding step (a), although Anderson does not explicitly disclose a single embodiment of contacting with an effective amount of interferon (IFN)y, tumor necrosis factor (TNF)α, interleukin (IL)-1 b, and IL-17, Anderson discloses each of these as inflammatory agent options and Anderson discloses combinations (“stimulation is achieved with one or more inflammatory agents” para. [0129]). Therefore, one of ordinary skill would have at once envisaged this specific combination from the limited options of inflammatory agents and inflammatory agent combinations disclosed by Anderson, and Anderson anticipates instant claims. Applicant is directed to MPEP 2131.02 which states that a reference disclosure can anticipate a claim when the reference describes the limitations but "'d[oes] not expressly spell out' the limitations as arranged or combined as in the claim, if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination." Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381, 114 USPQ2d 1250, 1254 (Fed. Cir. 2015) (quoting In re Petering, 301 F.2d 676, 681(CCPA 1962))(see MPEP 2131.02).
Regarding claim 3, further to the discussion of claim 1 above, Anderson discloses the culturing occurs for 40 hours, which includes culturing for 18-24 hours (“conditioned for 40 hours prior to vesicle isolation” Example 1 para. [0208]). Regarding claim 3, the passive recitation of “the culturing step occurs for” is interpreted as open-ended.
Regarding claim 5, further to the discussion of claim 1 above, this claim recites the contingent limitation “when the collecting step occurs multiple times, the duration between collecting steps is about 1 day, 2 days, 3 days, 4 days, or longer.” Applicant is directed to MPEP 2111.05 (II) which states that the broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. See Ex parte Schulhauser, Appeal 2013-007847 (PTAB April 28, 2016) for an analysis of contingent claim limitations in the context of both method claims and system claims. Therefore, in the instant case, because the multiple collecting step need not occur, the requirements of claim 5 are met by Anderson as discussed above.
Regarding claim 6, further to the discussion of claim 1 above, it is noted that the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited (e.g. exosomes collected at different times comprise substantially the same genotype and/or phenotype). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). See also MPEP 2111.04 that a “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure” and a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Additionally, as discussed above, Anderson discloses all the active method steps of the instantly claimed method and therefore the result of “exosomes collected at different times comprise substantially the same genotype and/or phenotype” would inherently the recitation of the taught steps. Lastly, as discussed above (see claim 5 rejection above), instant claims do not require an active method step of collecting exosomes at different times and therefore because the collecting step need not occur, the requirements of claim 6 are met by Anderson as discussed above.
Regarding claim 7, further to the discussion of claim 1 above, Anderson discloses the exosomes comprise the markers CD9, CD63, CD47 (para. [0162], and/or CD81 (see also Table 5 and claim 40).
Regarding claim 11, further to the discussion of claim 1 above, Anderson discloses the culturing step occurs in the presence of hypoxia or low oxygen conditions (para. [0008, 0012, 00120, 0189, 0240, 0247]; claim 1) which is a specific conditions of CO2, O2 and nitrogen. Anderson also discloses “gas mixture of 20% oxygen, 5% CO2, and 75% nitrogen which is a specific conditions of CO2, O2 and nitrogen (Example 3 para. [0242]).
Regarding claim 16, further to the discussion of claim 1 above, the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited (e.g. “the exosomes have enhanced control of T cell proliferation compared to exosomes produced from culture that does not comprise IFNy, TNFα, IL-lb, and IL-17”). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). See also MPEP 2111.04 that a “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure” and a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Additionally, as stated above, Anderson discloses all the active method steps of the instantly claimed method and therefore the result of “the exosomes have enhanced control of T cell proliferation compared to exosomes produced from culture that does not comprise IFNy, TNFα, IL-lb, and IL-17” would inherently follow the recitation of the disclosed steps.
Regarding claims 17-19, further to the discussion of claim 1 above, Anderson discloses the method occurs in an automated system that is a tangential flow filtration or TFF system (instant claim 17) (“tangential flow filtration” para. [0011, 0021, 0034, 0039, 0045, 0096, 0143, 0147, 0152, 0240]; claims 119, 158, 163, 176-178, 187, 192). Regarding claim 18, TFF systems are configured to comprise continuous perfusion of medium through the system. Regarding claim 19, TFF systems can either be open, closed, or semi-closed and one of ordinary skill would have at once envisaged closed or semi-closed from this limited genus of options (see MPEP 2131.02 for discussion on “at once envisage”).
Regarding claims 20-21, further to the discussion of claim 1 above, Anderson discloses the method occurs in a bioreactor (instant claim 20) that comprises multiple hollow fibers (instant claim 21) (see Example 3).
Regarding claim 23, further to the discussion of claims 1 and 20-21 above, Anderson discloses surfaces inside the bioreactor are modified to comprise one or more extracellular matrix proteins (“hollow fiber cartridge was coated with an extracellular matrix (ECM) protein coating” and “coatings also appropriate for use with this method include fibronectin, gelatin, vitronectin, matrigel, and collagen”; Example 3 para. [0242]).
Regarding claim 27, further to the discussion of claim 1 above, Anderson discloses cell culture conditions including low levels of serum with FBS, and Anderson discloses platelet lystates as substitute for FBS. Therefore, the media disclosed with FBS only is free of PLL (para. [0126]).
Regarding claim 29, further to the discussion of claim 1 above, Anderson discloses the cell culture medias, which include the media for step (a) may include L-alanyl-L-glutamine dipeptide (“Glutamax” ; para. [0113]).
Regarding claim 43, further to the discussion of claim 1 above, Anderson discloses the exosomes are loaded to comprise one or more therapeutic agents (“the cell-derived vesicles are complexed to therapeutic agents, which include, without limitation, polynucleotides such as RNA and/or DNA and/or polypeptides or proteins such as neutropic factors” para. [0010]; see also para. [0023, 0025, 0040, 0098, 0154, 0155, 0164]; claims 80-89).
Accordingly, by teaching all the limitations of claims 1, 3, 5-7, 11, 16-21, 23, 27, 29 and 43, Anderson anticipates instant claims.
Alternatively, regarding claims 1, 3, 5-7, 11, 16-21, 23, 27, 29 and 43, if the method is not directly anticipated because Anderson does not disclose a single specific embodiment of culturing with an effective amount of interferon (IFN)y, tumor necrosis factor (TNF)α, interleukin (IL)-1 b, and IL-17, the method is still prima facie obvious because the specific inflammatory agents of IFNy, TNFα, IL-1β and IL-17 are merely represent a simple combination of known prior art elements of inflammatory agents disclosed as options by Anderson which would have the predictable result of producing a pro-inflammatory response and/or trigger the stem cells to react to inflammation by producing anti-inflammatory agents, and producing an anti-inflammatory effect (para. [0090]) in the MSCS disclosed by Anderson.
Claim Rejections - 35 USC § 103
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.
Claims 1,3, 5-7, 11 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (J Cell Physiol. 2018 Sep;233(9):6832-6840. Epub 2018 Apr 11.; see IDS filed 8th, August, 2024; henceforth “Zhang”) in view of Najar et al. (Inflamm Res. 2019 Feb;68(2):167-176. Epub 2018 Nov 14.; henceforth “Najar”) and Han et al. (Cell Death Differ. 2014 Nov;21(11):1758-68. Epub 2014 Jul 18.; see IDS filed 24th, January, 2025; henceforth “Han”).
Regarding claim 1, a method of producing exosomes from mesenchymal stromal cells (MSCs), comprising the steps of:
(a) culturing MSCs in the presence of an effective amount of interferon (IFN)y (“umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr.” abstract; see also “2.2 | Preparation of conditioned medium” pg. 6834 col. 1);
and
(b) collecting the exosomes from the culture (pg. 6834 “2.3 | Exosome harvest”).
However, regarding claim 1, although Zhang teaches culturing MSCs in the presence of cytokines before collecting exosomes and Zhang teaches stimulation of MSCs with cytokines can help us obtain MSC-ex that contain more effective substances than traditional culture methods (pg. 6837 col. 2; Figure 7), Zhang is silent to culturing the MSCs in the presence of an effective amount of a proinflammatory cytokine cocktail containing effective amounts of IL-1β and TNF.
Nevertheless, regarding claim 1, Najar teaches a step of culturing (priming) MSCs in the presence of a proinflammatory cytokine cocktail containing effective amounts of IL-1β (25 ng/ml), TNF-α (50 ng/ ml), IFN-α (3000 U/ml or 10 ng/ml) and IFN-γ (1000 U/ ml or 50 ng/ml) (pg. 168 col. 2 last para. “Inflammation priming of BM‑MSCs”) to mimic inflammation in the MSCs (pg. 170 col. 1 1st para.). Najar teaches that under inflammatory conditions, MSCs are primed to become more immunomodulatory in inhibiting immune response by displaying a high level of immunoregulatory factors (e.g. PGE2, Galectin, etc.) (pg. 171 col. 2 2nd para.). Najar teaches the primed MSCs secrete great amounts of cyto-protective molecules (e.g. HO-1) and growth factors (e.g. HGF, TGF, etc.) which can facilitate tissue repair through their effects on endothelial cells and fibroblasts, as well as tissue progenitor cells, at sites of damaged tissue (pg. 171 col. 2 2nd para.).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Zhang, and combine the known prior art element of culturing the MSCs in the presence of an effective amount of IL-1β and TNF of Najar to obtain the predictable result of primed MSCs. One of ordinary skill would have been motivated to do so as taught by Najar to prime the MSCs to secrete great amounts of cyto-protective molecules (e.g. HO-1) and growth factors (e.g. HGF, TGF, etc.) (pg. 171 col. 2 2nd para.) that would be beneficial in the method of Zhang because Zhang teaches stimulation of MSCs with cytokines can help us obtain MSC-ex that contain more effective substances than traditional culture methods (pg. 6837 col. 2; Figure 7). Therefore, stimulating the MSCs with the IL-1β and TNF of Najar would allow production of MSC-ex that contain higher amounts of cyto-protective molecules and growth factors. Regarding the reasonable expectation of success, Zhang a step of evidences culturing MSCs with cytokines followed by a step of collecting MSCs from those exosomes (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”).
However, regarding claim 1, Zhang and Najar are silent to culturing MSCs in the presence of an effective amount of IL-17.
Nevertheless, regarding claim 1, Najar cites Han (pg. 174 col. 1 1st para.; citation 70). Han teaches culturing MSCs with the cytokine IL-17 enhanced the immunosuppressive effect of MSCs induced by IFN- γ and TNFα (abstract; see also Results pf. 1759 col. 2 and pg. 1760 col. 1). Han teaches IL-17 induces cytokine/chemokine gene expression in MSCs (pg. 1765).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggest by Zhang in view of Najar, and combine the known prior art element of culturing the MSCs in the presence of an effective amount of IL-17 of Najar to obtain the predictable result of primed MSCs. One of ordinary skill would have been motivated to do so as taught by Han to induces cytokine/chemokine gene expression in the MSCs (pg. 1765) and to enhance the immunosuppressive effect of MSCs induced by IFN- γ and TNFα (abstract; see also Results pf. 1759 col. 2 and pg. 1760 col. 1). Regarding the reasonable expectation of success, Zhang evidences a step of culturing MSCs with cytokines followed by a step of collecting MSCs from those exosomes (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”).
Regarding claim 3, further to the discussion of claim 1 above, Zhang teaches the culturing step occurs for 72 hours (“cytokine was added according to the test group for 72 hr.” pg. 6834 col. 1 5th para “2.2 | Preparation of conditioned medium”). 72 hours of culturing includes culturing which occurs for 18-24 hours. Regarding claim 3, the passive recitation of “the culturing step occurs for” is interpreted as open-ended.
Regarding claim 3, it is also noted that 72 hours is close to 24 hours of culturing. Applicant is directed to MPEP section 2144.05 which states 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 of "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."). in the instant case the taught 72 hours is so close to the claimed 24 hours that one of ordinary skill would have expected them to have the same properties.
Additionally, regarding claim 3, Applicant is reminded that generally, differences in timings will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such timing is critical (MPEP 2144.05 II).
Regarding claim 5, further to the discussion of claim 1 above, this claim recites the contingent limitation “when the collecting step occurs multiple times, the duration between collecting steps is about 1 day, 2 days, 3 days, 4 days, or longer.” Applicant is directed to MPEP 2111.05 (II) which states that the broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. See Ex parte Schulhauser, Appeal 2013-007847 (PTAB April 28, 2016) for an analysis of contingent claim limitations in the context of both method claims and system claims. Therefore, in the instant case, because the collecting step need not occur, the requirements of claim 5 are met by Zhang in view of Najar and Han as discussed above.
Regarding claim 6, further to the discussion of claim 1 above, it is noted that the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited (e.g. exosomes collected at different times comprise substantially the same genotype and/or phenotype). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). See also MPEP 2111.04 that a “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure” and a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Additionally, as discussed above, Zhang in view of Najar and Han suggest all the active method steps of the instantly claimed method and therefore the result of “exosomes collected at different times comprise substantially the same genotype and/or phenotype” would naturally follow the recitation of the taught steps. Lastly, as discussed above (see claim 5 rejection above), instant claims do not require an active method step of collecting exosomes at different times and therefore because the collecting step need not occur, the requirements of claim 6 are met by Zhang in view of Najar and Han as discussed above.
Regarding claim 7, further to the discussion of claim 1 above, Zhang teaches the exosomes comprise the markers CD9, CD63 and CD81 (Figure 3).
Regarding claim 11, further to the discussion of claim 1 above, Zhang teaches culturing conditions of 5% CO2 (pg. 6834 col. 1 3rd para. “2.1 | Cell culture”) which is a specific condition of CO2, O2 and nitrogen.
Regarding claim 16, further to the discussion of claim 1 above, it is noted that the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited (e.g. the exosomes have enhanced control of T cell proliferation compared to exosomes produced from culture that does not comprise IFNy, TNFoc, IL-lb, and IL-17). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. Additionally, as discussed above, Zhang in view of Najar and Han suggest all the active method steps of the instantly claimed method and therefore the result of “the exosomes have enhanced control of T cell proliferation compared to exosomes produced from culture that does not comprise IFNy, TNFoc, IL-lb, and IL-17” would naturally follow the recitation of the taught steps. Lastly, Zhang teaches the exosomes inhibited the proliferation of PBMCs (Figure 5), which include T-cells, and therefore the suggested exosomes would also be expected to inhibit the proliferation of T-cells which is a type of “control” of T-cell proliferation as claimed.
Hence, the claimed invention as a whole was prima facie obvious.
Claims 1, 3, 5-7, 11, 16-21, 23, 27, 33 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Shpall et al. (WO-2019/099927-A1; see IDS filed 14th, December, 2022; henceforth “Shpall1”) in view of Zhang et al. (J Cell Physiol. 2018 Sep;233(9):6832-6840. Epub 2018 Apr 11.; see IDS filed 8th, August, 2024; henceforth “Zhang”), Najar et al. (Inflamm Res. 2019 Feb;68(2):167-176. Epub 2018 Nov 14.; henceforth “Najar”) and Han et al. (Cell Death Differ. 2014 Nov;21(11):1758-68. Epub 2014 Jul 18.; see IDS filed 24th, January, 2025; henceforth “Han”) as evidenced by Frank et al. (Mater Sci Eng C Mater Biol Appl. 2019 Mar:96:77-85. Epub 2018 Oct 26.; henceforth “Frank”).
Regarding claim 1, Shpall1 discloses a method of producing exosomes from mesenchymal stromal cells (MSCs) (“methods of manufacturing clinical grade exosomes derived from mesenchymal stem cells (MSCs)” abstract; see also Examples 1-3; Claim 1; Figure 1A) , comprising the steps of:
(a) culturing MSCs;
and
collecting the exosomes from the culture (“isolating exosomes from the conditioned media fractions” para. [0005, 0016-0017, 0019-0020, 0023-0024, 0028, 0031, 0035-0036, 0042-0044, 0052-0054] and “D. Isolation of Exosomes” para. [0096-00104]; Figure 1A)
However, regarding claim 1, although Shpall1 teaches a step of culturing the MSCs before collecting the exosomes, Shpall1 is silent to a step of (a) culturing MSCs in the presence of an effective amount of interferon (IFN)y before the step of (b) collecting the exosomes from the culture.
Nevertheless, regarding claim 1, Zhang teaches a step of culturing MSCs in the presence of an effective amount of interferon (IFN)y before collecting exosomes from culture (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”). Zhang teaches the exosomes obtained from MSCs stimulated by IFN-γ had significant inhibitory effect on PBMCs (pg. 6837 col. 1 2nd para.; Figure 5). Zhang teaches exosomes obtained from MSCs stimulated by IFN-γ increase the proportion of T-regs (pg. 6837; Figure 6). Zhang teaches stimulation of MSCs with cytokines can help us obtain MSC-ex that contain more effective substances than traditional culture methods (pg. 6837 col. 2; Figure 7). Zhang teaches these results provide a direction and theoretical basis for pretreatment of MSCs to improve the efficacy of clinical immune regulation in the future (pg. 6839 col. 1 3rd para.).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Shpall1, and combine the known prior art element of the step of culturing the MSCs with a cytokine cocktail including IFN-γ of Zhang to obtain the predictable result of a method of producing exosomes from MSCs. One of ordinary skill would have been motivated to do so as taught by Zhang to obtain MSC derived exosomes that contain more effective substances than traditional culture methods (pg. 6837 col. 2; Figure 7), including MSCs that have the ability to increase the proportion of T-regs (pg. 6837; Figure 6). Regarding the reasonable expectation of success, Zhang evidences a step of culturing MSCs in the presence of an effective amount of interferon (IFN)y before collecting exosomes from culture (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”).
However, regarding claim 1, although, as stated above, Zhang teaches and makes obvious pre-treatment of the MSCs with cytokines, Shpall1 and Zhang are silent to culturing the MSCs in the presence of an effective amount of a proinflammatory cytokine cocktail containing effective amounts of IL-1β and TNF.
Nevertheless, regarding claim 1, Najar teaches a step of culturing (priming) MSCs in the presence of a proinflammatory cytokine cocktail containing effective amounts of IL-1β (25 ng/ml), TNF-α (50 ng/ ml), IFN-α (3000 U/ml or 10 ng/ml) and IFN-γ (1000 U/ ml or 50 ng/ml) (pg. 168 col. 2 last para. “Inflammation priming of BM‑MSCs”) to mimic inflammation in the MSCs (pg. 170 col. 1 1st para.). Najar teaches that under inflammatory conditions, MSCs are primed to become more immunomodulatory in inhibiting immune response by displaying a high level of immunoregulatory factors (e.g. PGE2, Galectin, etc.) (pg. 171 col. 2 2nd para.). Najar teaches the primed MSCs secrete great amounts of cyto-protective molecules (e.g. HO-1) and growth factors (e.g. HGF, TGF, etc.) which can facilitate tissue repair through their effects on endothelial cells and fibroblasts, as well as tissue progenitor cells, at sites of damaged tissue (pg. 171 col. 2 2nd para.).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Shpall1 in view of Zhang, and combine the known prior art element of culturing the MSCs in the presence of an effective amount of IL-1β and TNF of Najar to obtain the predictable result of primed MSCs. One of ordinary skill would have been motivated to do so as taught by Najar to prime the MSCs to secrete great amounts of cyto-protective molecules (e.g. HO-1) and growth factors (e.g. HGF, TGF, etc.) (pg. 171 col. 2 2nd para.) that would be beneficial because Zhang teaches stimulation of MSCs with cytokines can help us obtain MSC-ex that contain more effective substances than traditional culture methods (pg. 6837 col. 2; Figure 7). Therefore, stimulating the MSCs with the IL-1β and TNF of Najar would allow production of MSC-ex that contain higher amounts of cyto-protective molecules and growth factors. Regarding the reasonable expectation of success, Zhang evidences a step of evidences culturing MSCs with cytokines followed by a step of collecting MSCs from those exosomes (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”).
However, regarding claim 1, Shpall1, Zhang and Najar are silent to culturing MSCs in the presence of an effective amount of IL-17.
Nevertheless, regarding claim 1, Najar cites Han (pg. 174 col. 1 1st para.; citation 70). Han teaches culturing MSCs with the cytokine IL-17 enhanced the immunosuppressive effect of MSCs induced by IFN- γ and TNFα (abstract; see also Results pf. 1759 col. 2 and pg. 1760 col. 1). Han teaches IL-17 induces cytokine/chemokine gene expression in MSCs (pg. 1765).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggest by Shpall1 in view of Zhang and Najar, and combine the known prior art element of culturing the MSCs in the presence of an effective amount of IL-17 of Najar to obtain the predictable result of primed MSCs. One of ordinary skill would have been motivated to do so as taught by Han to induces cytokine/chemokine gene expression in the MSCs (pg. 1765) and to enhance the immunosuppressive effect of MSCs induced by IFN- γ and TNFα (abstract; see also Results pf. 1759 col. 2 and pg. 1760 col. 1). Regarding the reasonable expectation of success, Zhang a step of evidences culturing MSCs with cytokines followed by a step of collecting MSCs from those exosomes (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”).
Regarding claim 3, further to the discussion of claim 1 above, Zhang teaches the culturing step occurs for 72 hours (“cytokine was added according to the test group for 72 hr.” pg. 6834 col. 1 5th para “2.2 | Preparation of conditioned medium”) and it would therefore be obvious to use this culture duration with the suggested cytokines in the suggested method. 72 hours of culturing includes culturing which occurs for 18-24 hours. Regarding claim 3, the passive recitation of “the culturing step occurs for” is interpreted as open-ended.
Regarding claim 3, it is also noted that 72 hours is close to 24 hours of culturing. Applicant is directed to MPEP section 2144.05 which states 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 of "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."). In the instant case the taught 72 hours is so close to the claimed 24 hours that one of ordinary skill would have expected them to have the same properties.
Additionally, regarding claim 3, Applicant is reminded that generally, differences in timings will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such timing is critical (MPEP 2144.05 II).
Regarding claim 5, further to the discussion of claim 1 above, this claim recites the contingent limitation “when the collecting step occurs multiple times, the duration between collecting steps is about 1 day, 2 days, 3 days, 4 days, or longer.” Applicant is directed to MPEP 2111.05 (II) which states that the broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. See Ex parte Schulhauser, Appeal 2013-007847 (PTAB April 28, 2016) for an analysis of contingent claim limitations in the context of both method claims and system claims. Therefore, in the instant case, because the collecting step need not occur, the requirements of claim 5 are met by Shpall in view of Zhang, Najar and Han as discussed above.
Regarding claim 6, further to the discussion of claim 1 above, it is noted that the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited (e.g. exosomes collected at different times comprise substantially the same genotype and/or phenotype). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). See also MPEP 2111.04 that a “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure” and a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Additionally, as discussed above, Shpall in view of Zhang, Najar and Han suggest all the active method steps of the instantly claimed method and therefore the result of “exosomes collected at different times comprise substantially the same genotype and/or phenotype” would naturally follow the recitation of the taught steps. Lastly, as discussed above (see claim 5 rejection above), instant claims do not require an active method step of collecting exosomes at different times and therefore because the collecting step need not occur, the requirements of claim 6 are met by Shpall1 in view of Zhang, Najar and Han as discussed above.
Regarding claim 7, further to the discussion of claim 1 above, Shpall1 teaches the exosomes comprise the markers CD9, CD63, CD47 and/or CD81 (para. [0052, 00103, 00185, 00199]).
Regarding claim 11, further to the discussion of claim 1 above, Shpall1 teaches culturing conditions of 5% CO2 (para. [0060]) which is a specific condition of CO2, O2 and nitrogen.
Regarding claim 16, further to the discussion of claim 1 above, it is noted that the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited (e.g. the exosomes have enhanced control of T cell proliferation compared to exosomes produced from culture that does not comprise IFNy, TNFoc, IL-lb, and IL-17). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. Additionally, as discussed above, Shpall in view of Zhang, Najar and Han suggest all the active method steps of the instantly claimed method and therefore the result of “the exosomes have enhanced control of T cell proliferation compared to exosomes produced from culture that does not comprise IFNy, TNFoc, IL-lb, and IL-17” would naturally follow the recitation of the taught steps. Lastly, Zhang teaches exosomes activated by IFN-y inhibited the proliferation of PBMCs (Figure 5), which include T-cells, and therefore the suggested exosomes which have been activated by IFN-y, would also be expected to inhibit the proliferation of T-cells which is a type of “control” of T-cell proliferation as claimed.
Regarding claim 17, further to the discussion of claim 1 above, Shpall1 teaches the method occurs in an automated system (“Terumo Quantum Cell Expansion system is an automated hollow
fiber cell culture platform” para. [00179]; Example 1; see also para. [0009, 0042, 0090, 0098, 00194]; claim 9; Figure 1D).
Regarding claim 18, further to the discussion of claims 1 and 17 above, Shpall1 teaches the Terumo Quantum Cell Expansion system as stated above (“Terumo Quantum Cell Expansion system is an automated hollow fiber cell culture platform” para. [00179]; Example 1; see also para. [0009, 0042, 0090, 0098, 00194]; claim 9; Figure 1D) (see claim 17 rejection above). Frank evidences the Terumo Quantum Cell Expansion system disclosed by Shpall1 has tubes for moving medium and therefore meets the limitations of “configured to comprise continuous perfusion of medium through part of the system”(see Figure 1).
Regarding claim 19, further to the discussion of claims 1 and 17 above, Shpall1 teaches the Terumo Quantum Cell Expansion system as stated above (“Terumo Quantum Cell Expansion system is an automated hollow fiber cell culture platform” para. [00179]; Example 1; see also para. [0009, 0042, 0090, 0098, 00194]; claim 9; Figure 1D) (see claim 17 rejection above). The Terumo Quantum Cell Expansion system disclosed by Shpall1 is a closed system (“a functionally closed bioreactor, such as the Temmo Cell Expansion System” para. [0042] and “closed bioreactor” claim 8).
Regarding claim 20, further to the discussion of claim 1 above, Shpall1 teaches the method occurs in a bioreactor (“Terumo Quantum Cell Expansion system is an automated hollow fiber cell culture platform” para. [00179]; Example 1; see also para. [0009, 0042, 0090, 0098, 00194]; claim 9; Figure 1D; see also “bioreactor” para. [0005, 0008-0010, 0020-0021, 0023-0024, 0028, 0031-0035, 0040, 0042-0043, 0058, 0059, 0077-0078, 0080-0081, 0085, 0088-0092, 00104, 00179-00181, 00184-00185, 00194]; Figures 1A-D, 2-3, 4A-4B, 5A-5E, 10-D; Example 1; claims 1, 6, 8-9, 11).
Regarding claim 21, further to the discussion of claims 1 and 20 above, Shpall1 teaches the bioreactor comprises multiple hollow fibers (hollow fiber bioreactor para. [0009, 0058-0059, 0077-0078, 0088-0091, 00179]; Example 1; claims 8-9; see also Terumo cell expansion system; para. [00179]; Example 1; see also para. [0009, 0042, 0090, 0098, 00194]; claim 9; Figure 1D).
Regarding claim 23, further to the discussion of claim 1 above, Shpall1 teaches the surfaces inside the bioreactor are modified to comprise one or more extracellular matrix proteins (“coating
the bioreactor with an extracellular matrix protein, such as fibronectin” para. [0092]; see also para. [00194]; Figure 1A).
Regarding claim 27, further to the discussion of claim 1 above, Shpall1 teaches the step of collecting exosomes (instant step (b)) comprises utilizes media that lacks platelet lysate (“culturing the cells in media essentially free of PLT (e.g., free of PLT); collecting conditioned media fractions from the bioreactor; and isolating exosomes from the conditioned media fractions” para. [0005]).
Regarding claim 33, further to the discussion of claim 1 above, Shpall1 teaches step (b) of collecting the exosomes from the culture occurs every 48 hours, which is more than once (para. [0014] see also “The conditioned media fractions may be collected about 4- 10 times, such as about 5, 6, 7, or 8 times, particularly about 6 times” para. [0043] which are all embodiments of “more than once” as claimed.)
Regarding claim 43, further to the discussion of claim 1 above, Shpall1 teaches the exosomes are loaded to comprise one or more therapeutic agents (“loading the exosomes with therapeutic agents”; abstract; see also para. [0003, 0019, 0027, 0028, 0045, 0064, 0066-0068, 0078, 00105, 00107, 00109, 00117, 00122, 00124-00127, 00145-00146, 00149, 00150-00153, 00155, 00157-00158, 00175-00176, 00177]; claim 43-44, 69-71, 77).
Hence, the claimed invention as a whole was prima facie obvious.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Shpall et al. (WO-2019/099927-A1; see IDS filed 14th, December, 2022; henceforth “Shpall1”) in view of Zhang et al. (J Cell Physiol. 2018 Sep;233(9):6832-6840. Epub 2018 Apr 11.; see IDS filed 8th, August, 2024; henceforth “Zhang”), Najar et al. (Inflamm Res. 2019 Feb;68(2):167-176. Epub 2018 Nov 14.; henceforth “Najar”) and Han et al. (Cell Death Differ. 2014 Nov;21(11):1758-68. Epub 2014 Jul 18.; see IDS filed 24th, January, 2025; henceforth “Han”) as applied to claims 1 and 20-21 above, and in further view of ThermoFisher (2019, accessed at https://web.archive.org/web/20190721110130/https://www.thermofisher.com/us/en/home/life-science/cell-culture/mammalian-cell-culture/media-supplements/glutamax-media.html).
The teachings of Shpall1, Zhang, Najar and Han above are hereby incorporated in their entirety.
Regarding claim 29, further to the discussion of claim 1 above, although Shpall1 teaches the MSCs may be cultured in media comprising L-glutamine (para. [0082, 00180, 0192, 0194]; Example 4), Shpall1, Zhang, Najar, and Han are silent to the media comprising L-alanyl-L-glutamine dipeptide.
Nevertheless, regarding claim 29, ThermoFisher teaches L-alanyl-L-glutamine as a cell culture media supplement to provide the essential nutrient L-glutamine to cells without decomposing into ammonia, which is toxic to cells (GlutaMAXTM; pg. 1).
Therefore, regarding claim 29, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Shpall1 in view of Zhang, Najar, and Han and simply substitute the known prior art element of the L-alanyl-L-glutamine of ThermoFisher to obtain the predicable result of a media for culturing MSCs. One of ordinary skill would have been motivated to do so as taught by ThermoFisher because L-glutamine is an essential amino acid additive for cell culture, it serves as an auxiliary energy source, and it can be used by cells as a source of nitrogen for the synthesis of proteins and nucleic acids (pg. 1). Furthermore, one of ordinary skill would have been motivated to specifically substitute L-alanyl-L-glutamine (GlutaMAXTM) because it provides the benefits of L-glutamine in cell culture, but is more stable and does not spontaneously degrade (ThermoFisher pg. 1). Regarding the reasonable expectation of success, Shpall1 evidences preparation of medias for use in the method comprising L-glutamine (para. [0082, 00180, 0192, 0194]; Example 4) and therefore one of ordinary skill would have had a reasonable expectation of success for preparing the same medias for use in the method with the suggested L-alanyl-L-glutamine.
Hence, the claimed invention as a whole was prima facie obvious.
Claims 33 is rejected under 35 U.S.C. 103 as being unpatentable over Anderson et al. (WO-2018/226758-A2; henceforth “Anderson”) in view of over Shpall et al. (WO-2019/099927-A1; see IDS filed 14th, December, 2022; henceforth “Shpall1”).
The teachings of Anderson above are hereby incorporated in their entirety.
Regarding claim 33, further to the discussion of claim 1 above, Anderson is silent to whether the collection of exosomes from the culture occurs more than once in an interval of about 48 hours.
Nevertheless, regarding claim 33, Shpall teaches a step of collecting exosomes from the culture occurs every 48 hours, which is more than once (para. [0014] see also “The conditioned media fractions may be collected about 4- 10 times, such as about 5, 6, 7, or 8 times, particularly about 6 times” para. [0043] which are all embodiments of “more than once” as claimed.).
Therefore, regarding claim 33, further to the discussion of claim 1 above, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Anderson, and combine the known prior art element of collecting exosomes from the culture every 48 hours, which is more than once (para. [0014] see also “The conditioned media fractions may be collected about 4- 10 times, such as about 5, 6, 7, or 8 times, particularly about 6 times” para. [0043] which are all embodiments of “more than once” as claimed.) to obtain the predicable result of multiple exosome collections. Regarding the reasonable expectation of success, Shpall1 evidences a step of collecting exosomes from the culture every 48 hours (para. [0014]).
Hence, the claimed invention as a whole was prima facie obvious.
Claim 47 is rejected under 35 U.S.C. 103 as being unpatentable over Shpall et al. (WO-2019/099927-A1; see IDS filed 14th, December, 2022; henceforth “Shpall1”) in view of Zhang et al. (J Cell Physiol. 2018 Sep;233(9):6832-6840. Epub 2018 Apr 11.; see IDS filed 8th, August, 2024; henceforth “Zhang”), Najar et al. (Inflamm Res. 2019 Feb;68(2):167-176. Epub 2018 Nov 14.; henceforth “Najar”) and Han et al. (Cell Death Differ. 2014 Nov;21(11):1758-68. Epub 2014 Jul 18.; see IDS filed 24th, January, 2025; henceforth “Han”) as applied to claims 1 and 20-21 above, and in further view of Lopez-Lucas et al. (Cytotherapy. 2018 Sep;20(9):1110-1123. Epub 2018 Aug 29.; henceforth “Lopez-Lucas”).
The teachings of Shpall1, Zhang, Najar and Han above are hereby incorporated in their entirety.
Regarding claim 47, further to the discussion of claim 1 above, Shpall1, Zhang, Najar, and Han are silent to loading the exosomes with a fucosyl transferase by transfection.
Nevertheless, regarding claim 47, Lopez-Lucas teaches treating MSCs with fucosyltransferase (exofucosylated using a(1,3)-fucosyltransferases) to convert CD44 into HCELL and endow potent E-selectin binding without affecting viability or native phenotype (abstract; see also Results pg. 1114-1116 and Figures 1 and 4). Lopez-Lucas teaches Exofucosylation of hMSCs by treating them with fucosyltransferase to enforce the CD44 glycoform HCELL increases the tropism of hMSCs for E-selectin-expressing tissues, such as BM microvascular endothelium or inflamed tissue (Discussion pg. 1119 col. 2).
Additionally, regarding claim 47, Shpall1 teaches loading exosomes with cargo (abstract; para. [0003, 0019, 0023-0024, 0045-0046, 0078, 00105-00116, 00122, 00161]; claims 43, 48, 51, 62 and 65) by transfection (para. [0045, 00107-00108]; see in particular “Example 2 - Electroporation of Exosomes” para. [00186-00187]). Shpall 1 teaches the exosomes are CD44 positive (para. [0052]).
Therefore, regarding claim 47, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Shpall1 in view of Zhang, Najar and Han, and combine the known prior art element of the fucosyltransferase of Lopez-Lucas to obtain the predictable result of exofucosylated exosomes. One of ordinary skill would have been motivated to do so as taught by Lopez-Lucas to convert the CD44 on the exosomes into HCELL to endow potent E-selectin binding without affecting viability or native phenotype (abstract; see also Results pg. 1114-1116 and Figures 1 and 4) which would increases the tropism for E-selectin-expressing tissues, such as BM microvascular endothelium or inflamed tissue (Discussion pg. 1119 col. 2). This would have specifically been obvious to perform this step on the suggested exosomes because Shpall1 teaches they express CD44 (para. [0052]) and can be used to treat inflammatory disorders (para. [0122]; claim 63) and it would therefore be advantageous to increase the tropism of the exosomes for E-selectin-expressing inflamed tissue, as taught by Lopez-Lucas. Furthermore, it would have been obvious to load the exosomes with the fucosyltransferase by transfection because Shpall1 teaches this as a known method for loading exosomes (para. [0045, 00107-00108]; see in particular “Example 2 - Electroporation of Exosomes” para. [00186-00187]). Regarding the reasonable expectation of success, Lopez-Lucas evidences exofucosylation by treating with a(1,3)-fucosyltransferases (Methods pg. 1112-1113), and Shpall1 evidences loading exosomes with cargo (abstract; para. [0003, 0019, 0023-0024, 0045-0046, 0078, 00105-00116, 00122, 00161]; claims 43, 48, 51, 62 and 65) by transfection (para. [0045, 00107-00108]; see in particular “Example 2 - Electroporation of Exosomes” para. [00186-00187]). Therefore, one of ordinary skill would have had a reasonable expectation of success in loading the suggested fucosyltransferase into the suggested exosomes by the known transfection methods of Shpall1.
Hence, the claimed invention as a whole was prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Non-Statutory Double Patenting
U.S. Patent No. 11766402
Claims 1, 3, 5-7, 11, 16, 20, 21, 27, 33 and 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 12-13, 22-23 and 31-34 of US patent No. 11766402 (Shpall et al.; henceforth “Shpall2”) in view of Zhang et al. (J Cell Physiol. 2018 Sep;233(9):6832-6840. Epub 2018 Apr 11.; see IDS filed 8th, August, 2024; henceforth “Zhang”), Najar et al. (Inflamm Res. 2019 Feb;68(2):167-176. Epub 2018 Nov 14.; henceforth “Najar”) and Han et al. (Cell Death Differ. 2014 Nov;21(11):1758-68. Epub 2014 Jul 18.; see IDS filed 24th, January, 2025; henceforth “Han”)
The subject matter claimed in the instant application is disclosed in the referenced patent as
follows: the method of manufacturing exosomes from mesenchymal stem cells (MSCs) makes obvious the method of producing exosomes from mesenchymal stromal cells (MSCs) of instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claim 1, Shpall2 claims a method of producing exosomes from mesenchymal stromal cells (MSCs) (“manufacturing exosomes from mesenchymal stem cells (MSCs)”), comprising the steps of:
(a) culturing MSCs; and
(b) collecting the exosomes from the culture (“isolating exosomes from the conditioned media fractions”; claim 1).
However, regarding claim 1, Shpall2 does not claim culturing MSCs in the presence of an effective amount of interferon (IFN)y.
Nevertheless, regarding claim 1, Zhang teaches a step of culturing MSCs in the presence of an effective amount of interferon (IFN)y before collecting exosomes from culture (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”). Zhang teaches the exosomes obtained from MSCs stimulated by IFN-γ had significant inhibitory effect on PBMCs (pg. 6837 col. 1 2nd para.; Figure 5). Zhang teaches exosomes obtained from MSCs stimulated by IFN-γ increase the proportion of T-regs (pg. 6837; Figure 6). Zhang teaches stimulation of MSCs with cytokines can help us obtain MSC-ex that contain more effective substances than traditional culture methods (pg. 6837 col. 2; Figure 7). Zhang teaches these results provide a direction and theoretical basis for pretreatment of MSCs to improve the efficacy of clinical immune regulation in the future (pg. 6839 col. 1 3rd para.).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by Shpall2, and combine the known prior art element of the step of culturing the MSCs with a cytokine cocktail including IFN-γ of Zhang to obtain the predictable result of a method of producing exosomes from MSCs. One of ordinary skill would have been motivated to do so as taught by Zhang to obtain MSC derived exosomes that contain more effective substances than traditional culture methods (pg. 6837 col. 2; Figure 7), including MSCs that have the ability to increase the proportion of T-regs (pg. 6837; Figure 6). Regarding the reasonable expectation of success, Zhang evidences a step of culturing MSCs in the presence of an effective amount of interferon (IFN)y before collecting exosomes from culture (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”).
However, regarding claim 1, although, as stated above, Zhang teaches and makes obvious pre-treatment of the MSCs with cytokines, Shpall2 does not claim and Zhang is silent to culturing the MSCs in the presence of an effective amount of a proinflammatory cytokine cocktail containing effective amounts of IL-1β and TNF.
Nevertheless, regarding claim 1, Najar teaches a step of culturing (priming) MSCs in the presence of a proinflammatory cytokine cocktail containing effective amounts of IL-1β (25 ng/ml), TNF-α (50 ng/ ml), IFN-α (3000 U/ml or 10 ng/ml) and IFN-γ (1000 U/ ml or 50 ng/ml) (pg. 168 col. 2 last para. “Inflammation priming of BM‑MSCs”) to mimic inflammation in the MSCs (pg. 170 col. 1 1st para.). Najar teaches that under inflammatory conditions, MSCs are primed to become more immunomodulatory in inhibiting immune response by displaying a high level of immunoregulatory factors (e.g. PGE2, Galectin, etc.) (pg. 171 col. 2 2nd para.). Najar teaches the primed MSCs secrete great amounts of cyto-protective molecules (e.g. HO-1) and growth factors (e.g. HGF, TGF, etc.) which can facilitate tissue repair through their effects on endothelial cells and fibroblasts, as well as tissue progenitor cells, at sites of damaged tissue (pg. 171 col. 2 2nd para.).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by Shpall2 in view of Zhang, and combine the known prior art element of culturing the MSCs in the presence of an effective amount of IL-1β and TNF of Najar to obtain the predictable result of primed MSCs. One of ordinary skill would have been motivated to do so as taught by Najar to prime the MSCs to secrete great amounts of cyto-protective molecules (e.g. HO-1) and growth factors (e.g. HGF, TGF, etc.) (pg. 171 col. 2 2nd para.) that would be beneficial because Zhang teaches stimulation of MSCs with cytokines can help us obtain MSC-ex that contain more effective substances than traditional culture methods (pg. 6837 col. 2; Figure 7). Therefore, stimulating the MSCs with the IL-1β and TNF of Najar would allow production of MSC-ex that contain higher amounts of cyto-protective molecules and growth factors. Regarding the reasonable expectation of success, Zhang evidences a step of evidences culturing MSCs with cytokines followed by a step of collecting MSCs from those exosomes (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”).
However, regarding claim 1, Shpall2 does not claim and Zhang and Najar do not teach culturing the MSCs in the presence of an effective amount of IL-17.
Nevertheless, regarding claim 1, Han teaches culturing MSCs with the cytokine IL-17 enhanced the immunosuppressive effect of MSCs induced by IFN- γ and TNFα (abstract; see also Results pf. 1759 col. 2 and pg. 1760 col. 1). Han teaches IL-17 induces cytokine/chemokine gene expression in MSCs (pg. 1765).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by Shpall2 in view of Zhang and Najar, and combine the known prior art element of culturing the MSCs in the presence of an effective amount of IL-17 of Najar to obtain the predictable result of primed MSCs. One of ordinary skill would have been motivated to do so as taught by Han to induces cytokine/chemokine gene expression in the MSCs (pg. 1765) and to enhance the immunosuppressive effect of MSCs induced by IFN- γ and TNFα (abstract; see also Results pf. 1759 col. 2 and pg. 1760 col. 1). Regarding the reasonable expectation of success, Zhang a step of evidences culturing MSCs with cytokines followed by a step of collecting MSCs from those exosomes (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”).
Regarding claim 3, further to the discussion of claim 1 above, Shpall2 claims the culturing step occurs for 5-10 days (claim 12) or (8 days), which includes culturing for 18-24 hours. Regarding claim 3, the passive recitation of “the culturing step occurs for” is interpreted as open-ended.
Additionally, regarding claim 3, Applicant is reminded that generally, differences in timings will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such timing is critical (MPEP 2144.05 II).
Regarding claim 5, further to the discussion of claim 1 above, this claim recites the contingent limitation “when the collecting step occurs multiple times, the duration between collecting steps is about 1 day, 2 days, 3 days, 4 days, or longer.” Applicant is directed to MPEP 2111.05 (II) which states that the broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. See Ex parte Schulhauser, Appeal 2013-007847 (PTAB April 28, 2016) for an analysis of contingent claim limitations in the context of both method claims and system claims. Therefore, in the instant case, because the collecting step need not occur, the requirements of claim 5 are met by the method as claimed by Shpall2 in view of Zhang, Najar and Han as discussed above.
Regarding claim 6, further to the discussion of claim 1 above, it is noted that the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited (e.g. exosomes collected at different times comprise substantially the same genotype and/or phenotype). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). See also MPEP 2111.04 that a “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure” and a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Additionally, as discussed above, the method as claimed by Shpall2 in view of Zhang, Najar and Han suggest all the active method steps of the instantly claimed method and therefore the result of “exosomes collected at different times comprise substantially the same genotype and/or phenotype” would naturally follow the recitation of the taught steps. Lastly, as discussed above (see claim 5 rejection above), instant claims do not require an active method step of collecting exosomes at different times and therefore because the collecting step need not occur, the requirements of claim 6 are met by the method as claimed by Shpall2 in view of Zhang, Najar and Han as discussed above.
Regarding claim 7, further to the discussion of claim 1 above, Shpall2 does not claim the exosomes comprise the markers CD9, CD63, CD47, and/or CD81.
Nevertheless, regarding claim 7, the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited (e.g. the exosomes comprise the markers CD9, CD63, CD47, and/or CD81). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993). Additionally, as discussed above the method as claimed by Shpall2 in view of Zhang, Najar and Han includes all the active method steps of the instantly claimed method and therefore the result of that the exosomes comprise the markers CD9, CD63, CD47, and/or CD81 would naturally follow the recitation of the suggested steps.
Regarding claim 11, further to the discussion of claim 1 above, Shpall2 claims the cells are cultured at 5% oxygen, which is a specific conditions of CO2, O2 and nitrogen.
Regarding claim 16, further to the discussion of claim 1 above, Shpall2 does not claim the exosomes have enhanced control of T cell proliferation compared to exosomes produced from culture that does not comprise IFNy, TNFα, IL-lb, and IL-17.
Nevertheless, regarding claim 16, the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited. Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. Additionally, as discussed above the method as claimed by Shpall2 in view of Zhang, Najar and Han includes all the active method steps of the instantly claimed method and therefore the result of that the exosomes have enhanced control of T cell proliferation compared to exosomes produced from culture that does not comprise IFNy, TNFα, IL-lb, and IL-17 would naturally follow the recitation of the suggested steps.
Regarding claim 20, further to the discussion of claim 1 above, Shpall2 claims the method occurs in a bioreactor (claim 1).
Regarding claim 21, further to the discussion of claims 1 and 20 above, Shpall2 claims the bioreactor comprises multiple hollow fibers (claim 8).
Regarding claim 27, further to the discussion of claim 1 above, Shpall2 claims step (b) utilizes media that lacks platelet lysate (claim 1).
Regarding claim 33, further to the discussion of claim 1 above, Shpall2 claims at least 5 conditioned media fractions are collected (claim 23), and Shpall2 also claims he conditioned media fractions are collected for 10-14 days (claim 22). Therefore, it would be obvious to collect 5 fractions over the course of 10-14 days, which would be more than one collecting step with intervals of about 48 hours.
Regarding claim 43, further to the discussion of claim 1 above, Shpall2 claims the exosomes are loaded to comprise one or more therapeutic agents (claims 31-34).
Since the instant application claims are obvious over cited patent claims, in view of Zhang, Najar and Han, said claims are not patentably distinct.
Claims 17-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 12-13, 22-23 and 31-34 of US patent No. 11766402 (Shpall et al.; henceforth “Shpall2”) in view of Zhang et al. (J Cell Physiol. 2018 Sep;233(9):6832-6840. Epub 2018 Apr 11.; see IDS filed 8th, August, 2024; henceforth “Zhang”), Najar et al. (Inflamm Res. 2019 Feb;68(2):167-176. Epub 2018 Nov 14.; henceforth “Najar”) and Han et al. (Cell Death Differ. 2014 Nov;21(11):1758-68. Epub 2014 Jul 18.; see IDS filed 24th, January, 2025; henceforth “Han”) as applied to claim 1 above, and in further view of Anderson et al. (WO-2018/226758-A2; henceforth “Anderson”).
The teachings of Shpall2, Zhang, Najar, and Han are hereby incorporated in their entirety.
The subject matter claimed in the instant application is disclosed in the referenced patent as
follows: the method of manufacturing exosomes from mesenchymal stem cells (MSCs) makes obvious the method of producing exosomes from mesenchymal stromal cells (MSCs) of instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claims 17-18, further to the discussion of claim 1 above, Shpall2 does not claim the method occurs in an automated system.
Nevertheless, regarding claims 17-18, Anderson teaches methods of culturing MSCs and collecting exosomes using an automated system that is a tangential flow filtration or TFF system (instant claim 17) (“tangential flow filtration” para. [0011, 0021, 0034, 0039, 0045, 0096, 0143, 0147, 0152, 0240]; claims 119, 158, 163, 176-178, 187, 192).
Therefore, regarding claims 17-18, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by Shpall2 in view of Zhang, Najar, and Han and combine the known prior art element of the automated system of Anderson to obtain the predictable result of a method for culturing MSCs and collecting exosomes. Regarding the reasonable expectation of success, Anderson evidences methods of culturing MSCs and collecting exosomes using an automated system that is a tangential flow filtration or TFF system (instant claim 17) (“tangential flow filtration” para. [0011, 0021, 0034, 0039, 0045, 0096, 0143, 0147, 0152, 0240]; claims 119, 158, 163, 176-178, 187, 192).
Regarding claim 18, the TFF system suggested by Anderson is configured to comprise continuous perfusion of medium through the system.
Regarding claim 19, further to the discussion of claims 1 and 17 above, Shpall2 claims the system is closed (“functionally closed”; claim 1).
Since the instant application claims are obvious over cited patent claims, in view of Zhang, Najar and Han and in further view of Anderson, said claims are not patentably distinct.
Claim 23 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 12-13, 22-23 and 31-34 of US patent No. 11766402 (Shpall et al.; henceforth “Shpall2”) in view of Zhang et al. (J Cell Physiol. 2018 Sep;233(9):6832-6840. Epub 2018 Apr 11.; see IDS filed 8th, August, 2024; henceforth “Zhang”), Najar et al. (Inflamm Res. 2019 Feb;68(2):167-176. Epub 2018 Nov 14.; henceforth “Najar”) and Han et al. (Cell Death Differ. 2014 Nov;21(11):1758-68. Epub 2014 Jul 18.; see IDS filed 24th, January, 2025; henceforth “Han”) as applied to claim 1 above, and in further view of Frank et al. (Mater Sci Eng C Mater Biol Appl. 2019 Mar:96:77-85. Epub 2018 Oct 26.; henceforth “Frank”).
The teachings of Shpall2, Zhang, Najar, and Han are hereby incorporated in their entirety.
The subject matter claimed in the instant application is disclosed in the referenced patent as
follows: the method of manufacturing exosomes from mesenchymal stem cells (MSCs) makes obvious the method of producing exosomes from mesenchymal stromal cells (MSCs) of instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claim 23, further to the discussion of claims 1 and 20-21 above, although Shpall2 claims the method occurs in a bioreactor that comprises multiple hollow fibers Shpall2 does not claim and Zhang, Najar, and Han are silent to whether surfaces inside of the bioreactor are modified to comprise extracellular matrix proteins.
Nevertheless, regarding claim 23, Frank teaches the addition of a coating reagent to promote cell adherence is necessary to prepare the membrane surface of a hollow-fiber bioreactor for the culture of mesenchymal stem cells (abstract). Frank teaches coating the hollow-fiber bioreactor membrane with extracellular matrix components including options of fibronectin or vitronectin were successful as coating reagents for mesenchymal stem cells (abstract; see also Figure 4 and Materials and Methods pg. 79 col. 2 “2.3. Reagent preparation and coating of bioreactor”).
Therefore, regarding claim 23, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by Shpall2 in view of Zhang, Najar, and Han, and combine the known prior art element of coating the hollow-fiber bioreactor membrane with extracellular matrix components including of fibronectin or vitronectin to obtain the predictable result of a step of culturing MSCs. One of ordinary skill would have been motivated to do so as taught by Frank because Frank teaches the addition of a coating reagent to promote cell adherence is necessary to prepare the membrane surface of a hollow-fiber bioreactor for the culture of mesenchymal stem cells (abstract) and Frank specifically teaches options of fibronectin or vitronectin were successful as coating reagents for mesenchymal stem cells (abstract; see also Figure 4 and Materials and Methods pg. 79 col. 2 “2.3. Reagent preparation and coating of bioreactor”). Regarding the reasonable expectation of success, Frank evidences coating the hollow-fiber bioreactor membrane extracellular matrix components including options of fibronectin or vitronectin (abstract; see also Figure 4 and Materials and Methods pg. 79 col. 2 “2.3. Reagent preparation and coating of bioreactor”) and Frank evidences culturing MSCs in the system after coating with the ECM proteins (Figure 5; see also Materials and Methods pg. 79-80).
Since the instant application claims are obvious over cited patent claims, in view of Zhang, Najar and Han and in further view of Frank, said claims are not patentably distinct.
Claim 29 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 12-13, 22-23 and 31-34 of US patent No. 11766402 (Shpall et al.; henceforth “Shpall2”) in view of Zhang et al. (J Cell Physiol. 2018 Sep;233(9):6832-6840. Epub 2018 Apr 11.; see IDS filed 8th, August, 2024; henceforth “Zhang”), Najar et al. (Inflamm Res. 2019 Feb;68(2):167-176. Epub 2018 Nov 14.; henceforth “Najar”) and Han et al. (Cell Death Differ. 2014 Nov;21(11):1758-68. Epub 2014 Jul 18.; see IDS filed 24th, January, 2025; henceforth “Han”) as applied to claim 1 above, and in further view of ThermoFisher (2019, accessed at https://web.archive.org/web/20190721110130/https://www.thermofisher.com/us/en/home/life-science/cell-culture/mammalian-cell-culture/media-supplements/glutamax-media.html).
The teachings of Shpall2, Zhang, Najar, and Han are hereby incorporated in their entirety.
The subject matter claimed in the instant application is disclosed in the referenced patent as
follows: the method of manufacturing exosomes from mesenchymal stem cells (MSCs) makes obvious the method of producing exosomes from mesenchymal stromal cells (MSCs) of instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claim 29, further to the discussion of claim 1 above, Shpall2 does not claim and Zhang, Najar, and Han are silent to including L-alanyl-L-glutamine dipeptide the step of culturing the MSCs.
Nevertheless, regarding claim 29, ThermoFisher teaches L-alanyl-L-glutamine as a cell culture media supplement to provide the essential nutrient L-glutamine to cells without decomposing into ammonia, which is toxic to cells (GlutaMAXTM; pg. 1).
Therefore, regarding claim 29, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Shpall in view of Zhang, Najar, and Han and combine the known prior art element of the L-alanyl-L-glutamine of ThermoFisher to obtain the predicable result of a media for culturing MSCs. One of ordinary skill would have been motivated to do so as taught by ThermoFisher because L-glutamine is an essential amino acid additive for cell culture, it serves as an auxiliary energy source, and it can be used by cells as a source of nitrogen for the synthesis of proteins and nucleic acids (pg. 1). Furthermore, one of ordinary skill would have been motivated to specifically combine L-alanyl-L-glutamine (GlutaMAXTM) because it provides the benefits of L-glutamine in cell culture, but is more stable and does not spontaneously degrade (ThermoFisher pg. 1).
Since the instant application claims are obvious over cited patent claims, in view of Zhang, Najar and Han and in further view of ThermoFisher, said claims are not patentably distinct.
Claim 47 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 12-13, 22-23 and 31-34 of US patent No. 11766402 (Shpall et al.; henceforth “Shpall2”) in view of Zhang et al. (J Cell Physiol. 2018 Sep;233(9):6832-6840. Epub 2018 Apr 11.; see IDS filed 8th, August, 2024; henceforth “Zhang”), Najar et al. (Inflamm Res. 2019 Feb;68(2):167-176. Epub 2018 Nov 14.; henceforth “Najar”) and Han et al. (Cell Death Differ. 2014 Nov;21(11):1758-68. Epub 2014 Jul 18.; see IDS filed 24th, January, 2025; henceforth “Han”) as applied to claim 1 above, and in further view of Shpall et al. (WO-2019/099927-A1; see IDS filed 14th, December, 2022; henceforth “Shpall1”) and Lopez-Lucas et al. (Cytotherapy. 2018 Sep;20(9):1110-1123. Epub 2018 Aug 29.; henceforth “Lopez-Lucas”).
The teachings of Shpall2, Zhang, Najar, and Han are hereby incorporated in their entirety.
The subject matter claimed in the instant application is disclosed in the referenced patent as
follows: the method of manufacturing exosomes from mesenchymal stem cells (MSCs) makes obvious the method of producing exosomes from mesenchymal stromal cells (MSCs) of instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claim 47, further to the discussion of claim 1 above, Shpall2 does not claim and Zhang, Najar, and Han are silent to loading the exosomes with a fucosyl transferase by transfection.
Nevertheless, regarding claim 47, Lopez-Lucas teaches treating MSCs with fucosyltransferase (exofucosylated using a(1,3)-fucosyltransferases) to convert CD44 into HCELL and endow potent E-selectin binding without affecting viability or native phenotype (abstract; see also Results pg. 1114-1116 and Figures 1 and 4). Lopez-Lucas teaches Exofucosylation of hMSCs by treating them with fucosyltransferase to enforce the CD44 glycoform HCELL increases the tropism of hMSCs for E-selectin-expressing tissues, such as BM microvascular endothelium or inflamed tissue (Discussion pg. 1119 col. 2).
Additionally, regarding claim 47, Shpall1 teaches loading exosomes with cargo (abstract; para. [0003, 0019, 0023-0024, 0045-0046, 0078, 00105-00116, 00122, 00161]; claims 43, 48, 51, 62 and 65) by transfection (para. [0045, 00107-00108]; see in particular “Example 2 - Electroporation of Exosomes” para. [00186-00187]). Shpall 1 teaches exosomes from MSCs are CD44 positive (para. [0052]).
Therefore, regarding claim 47, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by Shpall2 in view of Zhang, Najar and Han, and combine the known prior art element of the fucosyltransferase of Lopez-Lucas to obtain the predictable result of exofucosylated exosomes. One of ordinary skill would have been motivated to do so as taught by Lopez-Lucas to convert the CD44 on the exosomes into HCELL to endow potent E-selectin binding without affecting viability or native phenotype (abstract; see also Results pg. 1114-1116 and Figures 1 and 4) which would increases the tropism for E-selectin-expressing tissues, such as BM microvascular endothelium or inflamed tissue (Discussion pg. 1119 col. 2). Additionally, it would have specifically been obvious to perform this step on the suggested exosomes because Shpall1 teaches exosomes from MSCs express CD44 (para. [0052]) and can be used to treat inflammatory disorders (para. [0122]; claim 63) and it would therefore be advantageous to increase the tropism of the exosomes for E-selectin-expressing inflamed tissue, as taught by Lopez-Lucas. Furthermore, it would have been obvious to load the exosomes with the fucosyltransferase by transfection because Shpall1 teaches this as a known method for loading exosomes (para. [0045, 00107-00108]; see in particular “Example 2 - Electroporation of Exosomes” para. [00186-00187]). Regarding the reasonable expectation of success, Lopez-Lucas evidences exofucosylation by treating with a(1,3)-fucosyltransferases (Methods pg. 1112-1113), and Shpall1 evidences loading exosomes with cargo (abstract; para. [0003, 0019, 0023-0024, 0045-0046, 0078, 00105-00116, 00122, 00161]; claims 43, 48, 51, 62 and 65) by transfection (para. [0045, 00107-00108]; see in particular “Example 2 - Electroporation of Exosomes” para. [00186-00187]). Therefore, one of ordinary skill would have had a reasonable expectation of success in loading the suggested fucosyltransferase into the suggested exosomes by the known transfection methods of Shpall1.
Since the instant application claims are obvious over cited patent claims, in view of Zhang, Najar and Han and in further view of Shpall1 and Lopez-Lucas, said claims are not patentably distinct.
Provisional Non-Statutory Double Patenting
U.S. Co-pending Application No. 18559667
Claims 1, 3, 5-7, 11, 16-21, 23, 27, 29 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 99-100, 102-103, 105 of copending application No. 18559667 (claims filed 2nd, December, 2025) in view of Zhang et al. (J Cell Physiol. 2018 Sep;233(9):6832-6840. Epub 2018 Apr 11.; see IDS filed 8th, August, 2024; henceforth “Zhang”), Najar et al. (Inflamm Res. 2019 Feb;68(2):167-176. Epub 2018 Nov 14.; henceforth “Najar”) and Han et al. (Cell Death Differ. 2014 Nov;21(11):1758-68. Epub 2014 Jul 18.; see IDS filed 24th, January, 2025; henceforth “Han”).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the method of producing therapeutic exosomes makes obvious the method of instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claim 1, U.S. Co-pending App ‘667 claims a method of producing exosomes from mesenchymal stromal cells (MSCs) (“method of producing therapeutic exosomes” claim 99), comprising the steps of:
(a) culturing MSCs; and
(b) collecting the exosomes from the culture (claim 99).
However, regarding claim 1, U.S. Co-pending App ‘667 does not claim culturing MSCs in the presence of an effective amount of interferon (IFN)y.
Nevertheless, regarding claim 1, Zhang teaches a step of culturing MSCs in the presence of an effective amount of interferon (IFN)y before collecting exosomes from culture (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”). Zhang teaches the exosomes obtained from MSCs stimulated by IFN-γ had significant inhibitory effect on PBMCs (pg. 6837 col. 1 2nd para.; Figure 5). Zhang teaches exosomes obtained from MSCs stimulated by IFN-γ increase the proportion of T-regs (pg. 6837; Figure 6). Zhang teaches stimulation of MSCs with cytokines can help us obtain MSC-ex that contain more effective substances than traditional culture methods (pg. 6837 col. 2; Figure 7). Zhang teaches these results provide a direction and theoretical basis for pretreatment of MSCs to improve the efficacy of clinical immune regulation in the future (pg. 6839 col. 1 3rd para.).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by U.S. Co-pending App ‘667, and combine the known prior art element of the step of culturing the MSCs with a cytokine cocktail including IFN-γ of Zhang to obtain the predictable result of a method of producing exosomes from MSCs. One of ordinary skill would have been motivated to do so as taught by Zhang to obtain MSC derived exosomes that contain more effective substances than traditional culture methods (pg. 6837 col. 2; Figure 7), including MSCs that have the ability to increase the proportion of T-regs (pg. 6837; Figure 6). Regarding the reasonable expectation of success, Zhang evidences a step of culturing MSCs in the presence of an effective amount of interferon (IFN)y before collecting exosomes from culture (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”).
However, regarding claim 1, although, as stated above, Zhang teaches and makes obvious pre-treatment of the MSCs with cytokines, U.S. Co-pending App ‘667 does not claim and Zhang is silent to culturing the MSCs in the presence of an effective amount of a proinflammatory cytokine cocktail containing effective amounts of IL-1β and TNF.
Nevertheless, regarding claim 1, Najar teaches a step of culturing (priming) MSCs in the presence of a proinflammatory cytokine cocktail containing effective amounts of IL-1β (25 ng/ml), TNF-α (50 ng/ ml), IFN-α (3000 U/ml or 10 ng/ml) and IFN-γ (1000 U/ ml or 50 ng/ml) (pg. 168 col. 2 last para. “Inflammation priming of BM-MSCs”) to mimic inflammation in the MSCs (pg. 170 col. 1 1st para.). Najar teaches that under inflammatory conditions, MSCs are primed to become more immunomodulatory in inhibiting immune response by displaying a high level of immunoregulatory factors (e.g. PGE2, Galectin, etc.) (pg. 171 col. 2 2nd para.). Najar teaches the primed MSCs secrete great amounts of cyto-protective molecules (e.g. HO-1) and growth factors (e.g. HGF, TGF, etc.) which can facilitate tissue repair through their effects on endothelial cells and fibroblasts, as well as tissue progenitor cells, at sites of damaged tissue (pg. 171 col. 2 2nd para.).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by U.S. Co-pending App ‘667 in view of Zhang, and combine the known prior art element of culturing the MSCs in the presence of an effective amount of IL-1β and TNF of Najar to obtain the predictable result of primed MSCs. One of ordinary skill would have been motivated to do so as taught by Najar to prime the MSCs to secrete great amounts of cyto-protective molecules (e.g. HO-1) and growth factors (e.g. HGF, TGF, etc.) (pg. 171 col. 2 2nd para.) that would be beneficial because Zhang teaches stimulation of MSCs with cytokines can help us obtain MSC-ex that contain more effective substances than traditional culture methods (pg. 6837 col. 2; Figure 7). Therefore, stimulating the MSCs with the IL-1β and TNF of Najar would allow production of MSC-ex that contain higher amounts of cyto-protective molecules and growth factors. Regarding the reasonable expectation of success, Zhang evidences a step of evidences culturing MSCs with cytokines followed by a step of collecting MSCs from those exosomes (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”).
However, regarding claim 1, U.S. Co-pending App ‘667 does not claim and Zhang and Najar do not teach culturing the MSCs in the presence of an effective amount of IL-17.
Nevertheless, regarding claim 1, Han teaches culturing MSCs with the cytokine IL-17 enhanced the immunosuppressive effect of MSCs induced by IFN- γ and TNFα (abstract; see also Results pf. 1759 col. 2 and pg. 1760 col. 1). Han teaches IL-17 induces cytokine/chemokine gene expression in MSCs (pg. 1765).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by U.S. Co-pending App ‘667 in view of Zhang and Najar, and combine the known prior art element of culturing the MSCs in the presence of an effective amount of IL-17 of Najar to obtain the predictable result of primed MSCs. One of ordinary skill would have been motivated to do so as taught by Han to induces cytokine/chemokine gene expression in the MSCs (pg. 1765) and to enhance the immunosuppressive effect of MSCs induced by IFN- γ and TNFα (abstract; see also Results pf. 1759 col. 2 and pg. 1760 col. 1). Regarding the reasonable expectation of success, Zhang a step of evidences culturing MSCs with cytokines followed by a step of collecting MSCs from those exosomes (abstract “umbilical cord-derived MSCs were treated with PBS, TGF-β, IFN-γ, or TGF-β plus IFN-γ for 72 hr. Then, exosomes were isolated from the culture supernatants”; see also pg. 6834 Materials and Methods “Preparation of conditioned medium” and “Exosome harvest”).
Regarding claim 3, further to the discussion of claim 1 above, U.S. Co-pending App ‘667 is silent to the culture length timing.
Nevertheless, regarding claim 3, Zhang teaches the culturing step occurs for 72 hours (“cytokine was added according to the test group for 72 hr.” pg. 6834 col. 1 5th para “2.2 | Preparation of conditioned medium”) and it would therefore be obvious to use this culture duration with the suggested cytokines in the suggested method. 72 hours of culturing includes culturing which occurs for 18-24 hours. Regarding claim 3, the passive recitation of “the culturing step occurs for” is interpreted as open-ended.
Regarding claim 3, it is also noted that 72 hours is close to 24 hours of culturing. Applicant is directed to MPEP section 2144.05 which states 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 of "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."). in the instant case the taught 72 hours is so close to the claimed 24 hours that one of ordinary skill would have expected them to have the same properties.
Additionally, regarding claim 3, Applicant is reminded that generally, differences in timings will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such timing is critical (MPEP 2144.05 II).
Regarding claim 5, further to the discussion of claim 1 above, this claim recites the contingent limitation “when the collecting step occurs multiple times, the duration between collecting steps is about 1 day, 2 days, 3 days, 4 days, or longer.” Applicant is directed to MPEP 2111.05 (II) which states that the broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. See Ex parte Schulhauser, Appeal 2013-007847 (PTAB April 28, 2016) for an analysis of contingent claim limitations in the context of both method claims and system claims. Therefore, in the instant case, because the collecting step need not occur, the requirements of claim 5 are met by the method as claimed by U.S. Co-pending App ‘667 in view of Zhang, Najar and Han as discussed above.
Regarding claim 6, further to the discussion of claim 1 above, it is noted that the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited (e.g. exosomes collected at different times comprise substantially the same genotype and/or phenotype). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). See also MPEP 2111.04 that a “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure” and a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Additionally, as discussed above, the method as claimed by U.S. Co-pending App ‘667 in view of Zhang, Najar and Han includes all the active method steps of the instantly claimed method and therefore the result of “exosomes collected at different times comprise substantially the same genotype and/or phenotype” would naturally follow the recitation of the taught steps. Lastly, as discussed above (see claim 5 rejection above), instant claims do not require an active method step of collecting exosomes at different times and therefore because the collecting step need not occur, the requirements of claim 6 are met by the method as claimed by U.S. Co-pending App ‘667 in view of Zhang, Najar and Han as discussed above.
Regarding claim 7, further to the discussion of claim 1 above, U.S. Co-pending App ‘667 does not claim the exosomes comprise the markers CD9, CD63, CD47, and/or CD81.
Nevertheless, regarding claim 7, the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited (e.g. the exosomes comprise the markers CD9, CD63, CD47, and/or CD81). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993). Additionally, as discussed above the method as claimed by U.S. Co-pending App ‘667 in view of Zhang, Najar and Han includes all the active method steps of the instantly claimed method and therefore the result of that the exosomes comprise the markers CD9, CD63, CD47, and/or CD81 would naturally follow the recitation of the suggested steps.
Regarding claim 11, further to the discussion of claim 1 above, U.S. Co-pending App ‘667 claims the culturing step (a) occurs in the presence of 5% CO2, 20% O2, and conditions balanced with nitrogen (claim 100) which is specific conditions of CO2, O2 and nitrogen.
Regarding claim 16, further to the discussion of claim 1 above, U.S. Co-pending App ‘667 does not claim the exosomes have enhanced control of T cell proliferation compared to exosomes produced from culture that does not comprise IFNy, TNFα, IL-lb, and IL-17.
Nevertheless, regarding claim 16, the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited. Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. Additionally, as discussed above the method as claimed by U.S. Co-pending App ‘667 in view of Zhang, Najar and Han includes all the active method steps of the instantly claimed method and therefore the result of that the exosomes have enhanced control of T cell proliferation compared to exosomes produced from culture that does not comprise IFNy, TNFα, IL-lb, and IL-17 would naturally follow the recitation of the suggested steps.
Regarding claims 17-18, further to the discussion of claim 1 above, U.S. Co-pending App ‘667 claims the method occurs in an automated system (instant claim 17), that is configured to comprise continuous perfusion of medium through at least part of the system (instant claim 18) (claim 102).
Regarding claim 19, further to the discussion of claims 1 and 17 above, although U.S. Co-pending App ‘667 does not claim whether the system is closed or semi-closed, the system may only open, closed, or semi-closed and one of ordinary skill would have at once envisaged closed or semi-closed from these limited options.
Regarding claims 20-21, further to the discussion of claim 1 above, U.S. Co-pending App ‘667 claims the method occurs in a bioreactor (claim 102) (instant claim 20), that is modified to allow adherence of cells (claim 102) (instant claim 21).
Regarding claim 23, further to the discussion of claims 1 and 20-21 above, U.S. Co-pending App ‘667 claims surfaces inside the bioreactor are modified to comprise one or more extracellular matrix proteins (claim 103).
Regarding claim 27, further to the discussion of claim 1 above, U.S. Co-pending App ‘667 claims step (b) utilizes media that lacks platelet lysate (claim 105).
Regarding claim 29, further to the discussion of claim 1 above, U.S. Co-pending App ‘667 claims step (a) utilizes alpha MEM media, heparin, human platelet lysate, and L-alanylL-
glutamine dipeptide (claim 105).
Regarding claim 43, further to the discussion of claim 1 above, U.S. Co-pending App ‘667 claims the exosomes are loaded to comprise one or more therapeutic agents (claim 99).
Since the instant application claims are anticipated by or obvious over cited application claims, in view of Zhang, Najar, and Han, said claims are not patentably distinct.
Claim 33 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 99-100, 102-103, 105 of copending application No. 18559667 (claims filed 2nd, December, 2025) in view of Zhang et al. (J Cell Physiol. 2018 Sep;233(9):6832-6840. Epub 2018 Apr 11.; see IDS filed 8th, August, 2024; henceforth “Zhang”), Najar et al. (Inflamm Res. 2019 Feb;68(2):167-176. Epub 2018 Nov 14.; henceforth “Najar”) and Han et al. (Cell Death Differ. 2014 Nov;21(11):1758-68. Epub 2014 Jul 18.; see IDS filed 24th, January, 2025; henceforth “Han”) as applied to claim 1 above, and in further view of Shpall et al. (WO-2019/099927-A1; see IDS filed 14th, December, 2022; henceforth “Shpall1”).
The teachings of U.S. Co-pending App ‘667, Zhang, Najar, and Han are hereby incorporated in their entirety.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the method of producing therapeutic exosomes makes obvious the method of instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claim 33, further to the discussion of claim 1 above, U.S. Co-pending App ‘667 does not claim collection of exosomes from the culture occurs more than once in an interval of about 48 hours.
Nevertheless, regarding claim 33, Shpall1 teaches a step of collecting exosomes from the culture occurs every 48 hours, which is more than once (para. [0014] see also “The conditioned media fractions may be collected about 4- 10 times, such as about 5, 6, 7, or 8 times, particularly about 6 times” para. [0043] which are all embodiments of “more than once” as claimed.).
Therefore, regarding claim 33, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by U.S. Co-pending App ‘667 in view of Zhang, Najar and Han, and combine the known prior art element of collecting exosomes from the culture every 48 hours, which is more than once (para. [0014] see also “The conditioned media fractions may be collected about 4- 10 times, such as about 5, 6, 7, or 8 times, particularly about 6 times” para. [0043] which are all embodiments of “more than once” as claimed.) to obtain the predicable result of multiple exosome collections. Regarding the reasonable expectation of success, Shpall1 evidences a step of collecting exosomes from the culture every 48 hours (para. [0014]).
Since the instant application claims are anticipated by or obvious over cited application claims, in view of Zhang, Najar, and Han and in further view of Shpall1, said claims are not patentably distinct.
Claim 47 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 99-100, 102-103, 105 of copending application No. 18559667 (claims filed 2nd, December, 2025) in view of Zhang et al. (J Cell Physiol. 2018 Sep;233(9):6832-6840. Epub 2018 Apr 11.; see IDS filed 8th, August, 2024; henceforth “Zhang”), Najar et al. (Inflamm Res. 2019 Feb;68(2):167-176. Epub 2018 Nov 14.; henceforth “Najar”) and Han et al. (Cell Death Differ. 2014 Nov;21(11):1758-68. Epub 2014 Jul 18.; see IDS filed 24th, January, 2025; henceforth “Han”) as applied to claim 1 above, and in further view of Shpall et al. (WO-2019/099927-A1; see IDS filed 14th, December, 2022; henceforth “Shpall1”) and Lopez-Lucas et al. (Cytotherapy. 2018 Sep;20(9):1110-1123. Epub 2018 Aug 29.; henceforth “Lopez-Lucas”).
The teachings of U.S. Co-pending App ‘667, Zhang, Najar, and Han are hereby incorporated in their entirety.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the method of producing therapeutic exosomes makes obvious the method of instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claim 47, further to the discussion of claim 1 above, U.S. Co-pending App ‘667 does not claim and Zhang, Najar, and Han are silent to treating the exosomes with a fucosyl transferase.
Nevertheless, regarding claim 47, Lopez-Lucas teaches treating MSCs with fucosyltransferase (exofucosylated using a(1,3)-fucosyltransferases) to convert CD44 into HCELL and endow potent E-selectin binding without affecting viability or native phenotype (abstract; see also Results pg. 1114-1116 and Figures 1 and 4). Lopez-Lucas teaches Exofucosylation of hMSCs by treating them with fucosyltransferase to enforce the CD44 glycoform HCELL increases the tropism of hMSCs for E-selectin-expressing tissues, such as BM microvascular endothelium or inflamed tissue (Discussion pg. 1119 col. 2).
Additionally, regarding claim 47, Shpall1 teaches loading exosomes with cargo (abstract; para. [0003, 0019, 0023-0024, 0045-0046, 0078, 00105-00116, 00122, 00161]; claims 43, 48, 51, 62 and 65) by transfection (para. [0045, 00107-00108]; see in particular “Example 2 - Electroporation of Exosomes” para. [00186-00187]). Shpall 1 teaches exosomes from MSCs are CD44 positive (para. [0052]).
Therefore, regarding claim 47, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as claimed by method as claimed by U.S. Co-pending App ‘667 in view of Zhang, Najar and Han, and combine the known prior art element of the fucosyltransferase of Lopez-Lucas to obtain the predictable result of exofucosylated exosomes. One of ordinary skill would have been motivated to do so as taught by Lopez-Lucas to convert the CD44 on the exosomes into HCELL to endow potent E-selectin binding without affecting viability or native phenotype (abstract; see also Results pg. 1114-1116 and Figures 1 and 4) which would increases the tropism for E-selectin-expressing tissues, such as BM microvascular endothelium or inflamed tissue (Discussion pg. 1119 col. 2). Additionally, it would have specifically been obvious to perform this step on the suggested exosomes because Shpall1 teaches exosomes from MSCs express CD44 (para. [0052]) and can be used to treat inflammatory disorders (para. [0122]; claim 63) and it would therefore be advantageous to increase the tropism of the exosomes for E-selectin-expressing inflamed tissue, as taught by Lopez-Lucas. Furthermore, it would have been obvious to load the exosomes with the fucosyltransferase by transfection because Shpall1 teaches this as a known method for loading exosomes (para. [0045, 00107-00108]; see in particular “Example 2 - Electroporation of Exosomes” para. [00186-00187]). Regarding the reasonable expectation of success, Lopez-Lucas evidences exofucosylation by treating with a(1,3)-fucosyltransferases (Methods pg. 1112-1113), and Shpall1 evidences loading exosomes with cargo (abstract; para. [0003, 0019, 0023-0024, 0045-0046, 0078, 00105-00116, 00122, 00161]; claims 43, 48, 51, 62 and 65) by transfection (para. [0045, 00107-00108]; see in particular “Example 2 - Electroporation of Exosomes” para. [00186-00187]). Therefore, one of ordinary skill would have had a reasonable expectation of success in loading the suggested fucosyltransferase into the suggested exosomes by the known transfection methods of Shpall1.
Since the instant application claims are obvious over cited patent claims, in view of Zhang, Najar and Han and in further view of Shpall1 and Lopez-Lucas, said claims are not patentably distinct.
Conclusion
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632