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 .
Detailed Action
This action is in response to the papers filed January 21, 2026.
Amendments
Applicant's response and amendments, filed January 21, 2026, to the prior Office Action is acknowledged. Applicant has cancelled Claims 2, 5-7, 10-33, 36-39, 41, and 44-46, and amended Claims 1 and 3-4.
Claims 1, 3-4, 8-9, 34-35, 40, and 42-43 are pending.
Election/Restrictions
Applicant has elected the following species, wherein:
i) the alternative cell marker species is expression of CD73, does not express CD3, and less than 50% of the cells express DC200, as recited in Claims 19-22, respectively;
ii) no election of the alternative cell source species; and
iii) the alternative administration route species is intranasal.
Claims 1, 3-4, 8-9, 34-35, 40, and 42-43 are pending and under examination.
Priority
This application is a 371 of PCT/IB2018/055473 filed on July 23, 2018. Applicant’s claim for the benefit of a prior-filed application provisional application 62/535,899, filed on July 23, 2017 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d). A copy of PCT/IB2018/055473, now published WO 19/021158, is filed with the instant application.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, Application No. 62/535,899, filed on July 23, 2017 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
With respect to Claim 1, Applicant’s provisional application 62/535,899 fails to disclose a method of treating an addiction in a subject in need thereof, the method comprising the step(s) of:
i) administering intranasally to the subject a pharmaceutical composition comprising placental adherent stromal cells (ASC),
wherein said ASC have been incubated in a 3D culture apparatus comprising microcarriers,
thereby treating the addiction.
62/535,899 is silent to the step of incubating placental ASCs in a 3D culture apparatus comprising microcarriers.
At best, 62/535,899 discloses the step of incubating bone marrow-derived MSCs in 2D culture (100mm2 dishes; pg 9, MSCs isolation) prior to intravenous or intranasal administration (e.g. pg 16, Example 1).
Applicant’s provisional application also fails to disclose the limitations of administering the ASCs within 1-72, 3-48, and/or 6-24 hours after the subject’s last exposure to the dopamine reuptake inhibitor, as recited in Claims 1 and 34-35.
Applicant’s provisional application also fails to disclose the limitations of an ASC cell population comprising 60-90% maternal ASCs, at least 80%, 85%, or 90% maternal ASCs, and/or a mixture of fetal and maternal ASCs, as recited in Claims 1 and 40-43.
Applicant’s provisional application also fails to disclose the limitations of Claims 3-4, and 8-9.
Claim 1 has been amended to recite a method of treating a cocaine addiction in a human subject, the method comprising the step(s) of:
administering intranasally to said subject a therapeutically effective amount of a pharmaceutical composition of ASCs comprising at least 80% maternal ASCs 1-72 hours after the subject’s last exposure to the cocaine,
wherein the subject has reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs,
thereby treating the cocaine addiction.
Claim 1 has also been amended to recite wherein the ASCs have been incubated in a 3D culture apparatus comprising microcarriers, and wherein at least 98% of the ASCs do not differentiate into adipocytes or osteocytes.
Clear support for the new limitation(s) cannot be found in the instant application or priority documents.
62/535,899, filed on July 23, 2017, is silent to the instantly recited limitations.
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
Original disclosure may not be relied upon unless it “constitute[s] a full, clear, concise and exact description” of the invention claimed in the patent to one of ordinary skill. In re Wertheim, 646 F.2d 527, 538–39 (CCPA 1981).
For genus claims, which are present here, we have looked for blaze marks within the disclosure that guide attention to the claimed species or subgenus. In re Ruschig, 379 F.2d 990, 994–95 (CCPA 1967); Fujikawa v. Wattana-sin, 93 F.3d 1559, 1571 (Fed. Cir. 1996); see also Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326–27 (Fed. Cir. 2000).
Following this maze-like path, each step providing multiple alternative paths, is not a written description of what might have been described if each of the optional steps had been set forth as the only option. This argument calls to mind what Yogi Berra, the Yankee catcher, was reported to have said: “when one comes to a fork in the road, take it.” That comment was notable because of its indeterminacy, its lack of direction. Similarly, here, all those optional choices do not define the intended result of the instant combination of specific method step parameters.
Clearly, however, just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety. Were this the case, a “laundry list” disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not “reasonably lead” those skilled in the art to any particular species.
Indeed, the listings of possibilities are so long, and so interwoven, that it is quite unclear how many compounds actually fall within the described genera and subgenera.
As explained by the Board, “[t]hese blaze marks must be clear because ‘it is easy to bypass a tree in the forest, even one that lies close to the trail.’” Decision at *10 (citing Fujikawa, 93 F.3d at 1571).
The Board concluded that, “[i]n this case, we find the point at which one must leave the trail to find the tree is not well marked in PCT/IB2018/055473 filed on July 23, 2018. Thus, PCT/IB2018/055473 filed on July 23, 2018 does not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
In the instant case, instant Claim 1 encompasses a cellular composition comprising at least 80% maternal ASCs and 20% fetal ASCs, as evidenced by Claim 40 (mixture of fetal and maternal ASCs), wherein at least 98% of the ASCs do not differentiate into adipocytes or osteocytes.
Instant claim fails to recite the culture method step parameters that necessarily and predictably achieve these limitations.
The disclosure of PCT/IB2018/055473 provides in boiler-plate form a genus of different % values of maternal ASCs and/or % values of fetal ASCs (e.g. pg 17, para 3; pg 18, para 2, “20-80% fetal cells”, “20-80% maternal cells”). However, these paragraphs are silent to the limitation wherein at least 98% of the ASCs do not differentiate into adipocytes or osteocytes, and the required the culture method step parameters that necessarily and predictably achieve these limitations.
The disclosure of PCT/IB2018/055473 provides contemplation of placental ASCs that do not differentiate into adipocytes under conditions where mesenchymal stem cells would differentiate into adipocytes. However, such ASCs are a sub-population of the instantly recited placental ASCs recited at a high level of generality in that the referenced placental ASCs having this functional property are a subset of ASCs for which more than 90% of the ASCs in the cell population express a combination of three specific markers and less than 3% of the ASCs in the cell population do not express a combination of five specific markers (e.g. pg 36, para 2).
The disclosure of PCT/IB2018/055473 provides contemplation of placental ASCs that do not differentiate into osteocytes under conditions where mesenchymal stem cells would differentiate into osteocytes. However, such ASCs are a sub-population of the instantly recited placental ASCs recited at a high level of generality in that the referenced placental ASCs having this functional property are a subset of ASCs for which more than 90% of the ASCs in the cell population express a combination of four specific markers and less than 5% of the ASCs in the cell population do not express a combination of three specific markers, which is a phenotypically different ASC population of cells than the ASC population that does not differentiate into adipocytes (e.g. pgs 37-38, joining para). Instant Claim 1 is vastly broader in scope than that disclosed by PCT/IB2018/055473.
PCT/IB2018/055473 is silent to a single population of cells comprising at least 80% maternal ASCs and 20% fetal ASCs, as evidenced by Claim 40 (mixture of fetal and maternal ASCs), wherein at least 98% of the ASCs do not differentiate into adipocytes or osteocytes, nor the culture method step parameters that necessarily and predictably achieve these limitations.
The priority documents fail to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the claims of the instant application.
The disclosures of the instant application, having the same specification as PCT/IB2018/055473, is similarly deficient.
Accordingly, the effective priority date of the instant claim set is granted as January 17, 2020, the filing date of the instant application.
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
New matter
1. Claim(s) 1, 3-4, 8-9, 34-35, 40, and 42-43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to recite a method of treating a cocaine addiction in a human subject, the method comprising the step(s) of:
administering intranasally to said subject a therapeutically effective amount of a pharmaceutical composition of ASCs comprising at least 80% maternal ASCs 1-72 hours after the subject’s last exposure to the cocaine,
wherein the subject has reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs,
thereby treating the cocaine addiction.
Claim 1 has also been amended to recite wherein the ASCs have been incubated in a 3D culture apparatus comprising microcarriers, and wherein at least 98% of the ASCs do not differentiate into adipocytes or osteocytes.
Clear support for the new limitation(s) cannot be found in the instant application or priority documents. Accordingly, the amendment(s) to Claim(s) 1 is/are considered to constitute new matter.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application”. MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure” (emphasis added).
62/535,899, filed on July 23, 2017, is silent to the instantly recited limitations.
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
Original disclosure may not be relied upon unless it “constitute[s] a full, clear, concise and exact description” of the invention claimed in the patent to one of ordinary skill. In re Wertheim, 646 F.2d 527, 538–39 (CCPA 1981).
For genus claims, which are present here, we have looked for blaze marks within the disclosure that guide attention to the claimed species or subgenus. In re Ruschig, 379 F.2d 990, 994–95 (CCPA 1967); Fujikawa v. Wattana-sin, 93 F.3d 1559, 1571 (Fed. Cir. 1996); see also Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326–27 (Fed. Cir. 2000).
Following this maze-like path, each step providing multiple alternative paths, is not a written description of what might have been described if each of the optional steps had been set forth as the only option. This argument calls to mind what Yogi Berra, the Yankee catcher, was reported to have said: “when one comes to a fork in the road, take it.” That comment was notable because of its indeterminacy, its lack of direction. Similarly, here, all those optional choices do not define the intended result of the instant combination of specific method step parameters.
Clearly, however, just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety. Were this the case, a “laundry list” disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not “reasonably lead” those skilled in the art to any particular species.
Indeed, the listings of possibilities are so long, and so interwoven, that it is quite unclear how many compounds actually fall within the described genera and subgenera.
As explained by the Board, “[t]hese blaze marks must be clear because ‘it is easy to bypass a tree in the forest, even one that lies close to the trail.’” Decision at *10 (citing Fujikawa, 93 F.3d at 1571).
The Board concluded that, “[i]n this case, we find the point at which one must leave the trail to find the tree is not well marked in PCT/IB2018/055473 filed on July 23, 2018. Thus, PCT/IB2018/055473 filed on July 23, 2018 does not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
In the instant case, instant Claim 1 encompasses a cellular composition comprising at least 80% maternal ASCs and 20% fetal ASCs, as evidenced by Claim 40 (mixture of fetal and maternal ASCs), wherein at least 98% of the ASCs do not differentiate into adipocytes or osteocytes.
Instant claim fails to recite the culture method step parameters that necessarily and predictably achieve these limitations.
The disclosure of PCT/IB2018/055473 provides in boiler-plate form a genus of different % values of maternal ASCs and/or % values of fetal ASCs (e.g. pg 17, para 3; pg 18, para 2, “20-80% fetal cells”, “20-80% maternal cells”). However, these paragraphs are silent to the limitation wherein at least 98% of the ASCs do not differentiate into adipocytes or osteocytes, and the required the culture method step parameters that necessarily and predictably achieve these limitations.
The disclosure of PCT/IB2018/055473 provides contemplation of placental ASCs that do not differentiate into adipocytes under conditions where mesenchymal stem cells would differentiate into adipocytes. However, such ASCs are a sub-population of the instantly recited placental ASCs recited at a high level of generality in that the referenced placental ASCs having this functional property are a subset of ASCs for which more than 90% of the ASCs in the cell population express a combination of three specific markers and less than 3% of the ASCs in the cell population do not express a combination of five specific markers (e.g. pg 36, para 2).
The disclosure of PCT/IB2018/055473 provides contemplation of placental ASCs that do not differentiate into osteocytes under conditions where mesenchymal stem cells would differentiate into osteocytes. However, such ASCs are a sub-population of the instantly recited placental ASCs recited at a high level of generality in that the referenced placental ASCs having this functional property are a subset of ASCs for which more than 90% of the ASCs in the cell population express a combination of four specific markers and less than 5% of the ASCs in the cell population do not express a combination of three specific markers, which is a phenotypically different ASC population of cells than the ASC population that does not differentiate into adipocytes (e.g. pgs 37-38, joining para). Instant Claim 1 is vastly broader in scope than that disclosed by PCT/IB2018/055473.
PCT/IB2018/055473 is silent to a single population of cells comprising at least 80% maternal ASCs and 20% fetal ASCs, as evidenced by Claim 40 (mixture of fetal and maternal ASCs), wherein at least 98% of the ASCs do not differentiate into adipocytes or osteocytes, nor the culture method step parameters that necessarily and predictably achieve these limitations.
The priority documents fail to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the claims of the instant application.
The disclosures of the instant application, having the same specification as PCT/IB2018/055473, is similarly deficient.
Applicant argues support for the amended claim is provided in instant application PGPub 2020/0155611, [0073-76, 79, and 153].
[0073-76] is/are silent to the culture conditions that give rise to a composition comprising at least 80% maternal ASCs, and in which at least 98% of the ASCs do not differentiate into adipocytes or osteocytes.
[0079] is silent to the culture conditions that give rise to a composition comprising at least 80% maternal ASCs, and in which at least 98% of the ASCs do not differentiate into adipocytes or osteocytes.
[0153] is silent to the culture conditions that give rise to a composition comprising at least 80% maternal ASCs, and in which at least 98% of the ASCs do not differentiate into adipocytes or osteocytes.
Alternatively, if Applicant believes that support for new limitation(s), as now recited in Claim(s) 1, is present and clearly envisaged in the instant application or earlier filed priority documents, applicant must, in responding to this Office Action, with particularity by page and line number where such support may be found.
Declarations and new references cannot demonstrate possession of a concept after the fact.
Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
2. Claim(s) 1, 3-4, 8-9, 34-35, 40, and 42-43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to recite a method of treating a cocaine addiction in a human subject, the method comprising the step(s) of:
administering intranasally to said subject a therapeutically effective amount of a pharmaceutical composition of ASCs comprising at least 80% maternal ASCs 1-72 hours after the subject’s last exposure to the cocaine,
wherein the subject has reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs,
thereby treating the cocaine addiction.
Claim 34 recites administering the ASCs intranasally to said subject 3-48 hours after the last exposure to the subject’s last exposure to the addictive dopamine reuptake inhibitor.
Claim 35 recites administering the ASCs intranasally to said subject 6-24 hours after the last exposure to the subject’s last exposure to the addictive dopamine reuptake inhibitor.
The claims denote that not all of the placental ASC cell populations that have been incubated in a 3D culture apparatus comprising microcarriers and administered intranasally 1-72, 3-48, and/or 6-24 hours after the subject’s last exposure to the addictive dopamine reuptake inhibitor will result in the phenotypic functional property of reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs.
The instant claims are considered to lack adequate written description for failing to recite the dosage of the pharmaceutical composition of ASCs that is to be administered intranasally 1-72 hours, 3-48, and/or 6-24 hours after the subject’s last exposure to the addictive dopamine reuptake inhibitor.
Claim 1 has also been amended to recite wherein the ASCs have been incubated in a 3D culture apparatus comprising microcarriers, and wherein at least 98% of the ASCs do not differentiate into adipocytes or osteocytes.
The claims denote that not all of the culture conditions in which the placental ASC cell populations have been incubated in a 3D culture apparatus comprising microcarriers will result in a cellular composition comprising the phenotypic property of at least 98% of the ASCs do not differentiate into adipocytes or osteocytes.
The instant claims are considered to lack adequate written description for failing to recite the culture condition(s) in which the placental ASC cell populations are to be incubated in a 3D culture apparatus comprising microcarriers that will necessarily and predictably result in a cellular composition comprising the phenotypic property of at least 98% of the ASCs do not differentiate into adipocytes or osteocytes.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs is dependent upon many different variable parameters, including, but not limited to:
the ASC formularies [parameter 1];
the ASC functional properties [parameter 2]; and
the dosage administered [parameter 3].
The claim(s) denote that there is an amount of the ASC pharmaceutical composition that, upon administration to the subject, is not, in fact, a therapeutically effective amount sufficient to necessarily and predictably achieve the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs.
Parameter 1
The claims are broad for reasonably encompassing an enormous genus of ASC formularies, whereby the pharmaceutical composition may comprise 80%-99.9% maternal ASCs of diverse HLA immunophenotypes and/or 1%-20% fetal ASCs of diverse HLA immunophenotypes, e.g. a ratio of 80-90% maternal cells to 10-20% fetal cells.
See 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, New Matter rejection above.
Parameter 2
The claims are broad for reasonably encompassing an enormous genus of functionally different ASC populations, whereby less than 3%, or at least 98%, of the ASCs:
do not differentiate into adipocytes (e.g pg 36);
do not differentiate into osteocytes (e.g. pg 37);
stimulate endothelial cell proliferation (e.g. pg 40);
stimulate T cell proliferation (e.g. pg 40);
inhibit T cell proliferation (e.g. pg 42);
promote angiogenesis (pg 40);
suppress an immune reaction in the subject (e.g. pg 41); and/or
promote neurogenesis (e.g. pg 42).
Applicant argues support for the amended claim is provided in instant application PGPub 2020/0155611, [0073-76, 79, and 153].
[0073-76] is/are silent to the culture conditions that give rise to a composition comprising at least 80% maternal ASCs, and in which at least 98% of the ASCs do not differentiate into adipocytes or osteocytes.
[0079] is silent to the culture conditions that give rise to a composition comprising at least 80% maternal ASCs, and in which at least 98% of the ASCs do not differentiate into adipocytes or osteocytes.
[0153] is silent to the culture conditions that give rise to a composition comprising at least 80% maternal ASCs, and in which at least 98% of the ASCs do not differentiate into adipocytes or osteocytes.
Instantly claimed cell population is directed to structurally and functionally different ASCs which suffer from lack of adequate written description. See discussions above in Priority and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, New Matter rejection.
Parameter 3
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the placental ASC cellular pharmaceutical comprising at least 80% maternal ASCs, and wherein at least 98% of the ASCs do not differentiate into adipocytes or osteocytes, must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public” for the treatment of addiction to cocaine.
The independent claim fails to recite the required minimum ASC cell number dosage comprising 80%-99.9% maternal ASCs of diverse HLA immunophenotypes and/or 1%-20% fetal ASCs of diverse HLA immunophenotypes, e.g. a ratio of 80-90% maternal cells to 10-20% fetal cells, and wherein at least 98% of the ASCs do not differentiate into adipocytes or osteocytes that is to be administered to the human subject so as to necessarily and predictably achieve a real-world, clinically meaningful treatment of cocaine addiction in a human subject.
While amended Claim 1 recites the ASCs comprise at least 80% maternal ASCs, such is uninformative as to the number of ASCs that are to be administered to the human subject so as to be therapeutically effective to achieve a real-world, clinically meaningful treatment for cocaine addiction.
To put it another way, while it is clear that the composition is to comprise at least 80% maternal ASCs, such speaks to the numerator, not the denominator (total cell number) in the thus-administered cellular pharmaceutical.
A composition of just 10 cells (denominator) yields only 8 (syn. at least 80%) maternal ASCs (numerator), for example.
While Example 11 discloses intranasal administration of an ASC composition to rat subjects, the example fails to disclose the structural [parameter 1] and functional [parameter 2] type(s) of ASCs is said composition, nor the ASC dosage [parameter 3] administered to the rat.
While Example 13 discloses intranasal administration of 1x10^6 ASCs [parameter 3] to rat subjects, the example fails to disclose the structural [parameter 1] and functional [parameter 2] type(s) of ASCs is said composition.
The working examples fail to disclose the phenotypic results of:
reduced neuroinflammation levels in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs; and
reduced extracellular levels of glutamate in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs.
Oppliger et al (Intranasal Delivery of Umbilical Cord-Derived Mesenchymal Stem Cells Preserves Myelination in Perinatal Brain Damage Stem Cells and Development 25(16): 1234-1242, 2016; of record) is considered relevant prior art for having taught a method of delivering human umbilical cord-derived mesenchymal stem cells to the brain of a rat subject suffering from ischemic injury (e.g. pg 1235, col. 1, “model of hypoxic-ischemic…brain damage”), the method comprising the step of intranasal administration of said UC-MSCs (e.g. Title), thereby treating the ischemic injury.
Oppliger et al taught that intranasal delivery of the MSCs to the brain is a promising, noninvasive therapeutic approach to restore the damaged brain (e.g. Abstract), as a less-invasive method is needed for some human patients and it avoids more invasive administration routes such as intracerebral or intrathecal administration (pgs 1234-1235, joining para).
Oppliger et al do not teach the human Wharton’s jelly mesenchymal stem cells are placental adherent stromal cells (syn. placenta-derived MSCs). However, Oppliger et al taught that the hWJ-MSCs express CD73, are negative for myeloid and hematopoietic cell-lineage specific markers, and are able to differentiate into osteocytes, chondrocytes, and adipocytes (e.g. pg 1235, col. 1, Materials and Methods, Human Wharton’s jelly mesenchymal stem cells), in accordance with the instantly claimed cells (specification pg 15, para 1-2).
The MSCs of Oppliger et al appear to be substantially the same, if not the same, mesenchymal stem/stromal cells as the instantly recited placental adherent stromal cells, even though the cells were isolated from human Wharton’s jelly tissue.
Since the Patent Office does not have the facilities for examining and comparing Applicant’s placental-derived MSCs with the MSCs of the prior art reference(s), the burden is upon applicants to show a distinction between the material structural and functional characteristics of the claimed compounds and the compounds of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
However, Oppliger et al do not teach wherein the intranasally administered MSCs (syn. ASCs) yield the phenotypic results of:
reduced neuroinflammation levels in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs; and
reduced extracellular levels of glutamate in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs.
Danielyan et al (Therapeutic Efficacy of Intranasally Delivered Mesenchymal Stem Cells in a Rat Model of Parkinson Disease, Rejuvenation Res. 14(1): 3-16, doi: 10.1089/rej.2010.1130; 2011; of record) is considered relevant prior art for having taught a method of treating Parkinson’s disease in a rat subject, the method comprising the step of administering to the subject via intranasal route a pharmaceutical composition comprising mesenchymal stem cells (syn. mesenchymal stromal cells), thereby treating the Parkinson’s disease (Title, Abstract; Figure 7).
Danielyan et al taught that the bone marrow-derived MSCs express CD73, are negative for myeloid and hematopoietic cell-lineage specific markers, and are able to differentiate into osteocytes, chondrocytes, and adipocytes (e.g. pg 4, col. 2, Materials and Methods, Isolation and cultivation of bone marrow MSCs), in accordance with the instantly claimed cells (specification pg 15, para 1-2).
The MSCs of Danielyan et al appear to be substantially the same, if not the same, mesenchymal stem/stromal cells as the instantly recited placental adherent stromal cells.
Since the Patent Office does not have the facilities for examining and comparing Applicant’s placental-derived MSCs with the MSCs of the prior art reference(s), the burden is upon applicants to show a distinction between the material structural and functional characteristics of the claimed compounds and the compounds of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
Danielyan et al taught that intranasal administration provides a highly promising noninvasive alternative to the traumatic surgical procedure of transplantation and allows targeted delivery of cells to the brain with the option of chronic application (Abstract).
Danielyan et al taught the MSCs were bone marrow-derived MSCs (e.g. pg 4, col. 2, Isolation and cultivation of bone marrow MSCs).
However, Danielyan et al do not teach wherein the intranasally administered MSCs (syn. ASCs) yield the phenotypic results of:
reduced neuroinflammation levels in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs; and
reduced extracellular levels of glutamate in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs.
Ezquer et al (Intravenous administration of anti-inflammatory mesenchymal stem cell spheroids reduces chronic alcohol intake and abolishes binge drinking, Scientific Reports 8: e4325, 15 pages, doi:10.1038/s41598-018-22750-7; available online March 22, 2018; of record) is considered relevant prior art for having taught a method of treating a rat subject suffering from substance abuse, to wit, alcohol, the method comprising the step of administering to the subject a pharmaceutical composition comprising human mesenchymal stem cells, wherein said MSCs were cultured under 3D conditions prior to administration, thereby successfully treating the subject (e.g. Abstract).
Ezquer et al taught that the 3D conditions greatly increased MSC anti-inflammatory ability and reduced cell volume, as compared to 2D culture conditions, enabling their access to the brain (e.g. Abstract).
Ezquer et al taught that neuroinflammation is associated with chronic alcohol use, as well as chronic use of addictive drugs, including psychostimulants such as cocaine, opiates, and methamphetamine (e.g. pg 1, Introduction). Chronic alcohol use is an art-recognized form of addiction.
However, Ezquer et al do not teach wherein the intranasally administered MSCs (syn. ASCs) yield the phenotypic results of:
reduced neuroinflammation levels in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs; and
reduced extracellular levels of glutamate in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs.
Pluristem (WO 11/132087; Applicant’s own work; of record in IDS; hereafter Pluristem-1) is considered relevant prior art for having disclosed culturing placental ASC in 3D culture.
However, Pluristem-1 do not disclose wherein the administered ASCs are administered intranasally, nor yield the phenotypic results of:
reduced neuroinflammation levels in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs; and
reduced extracellular levels of glutamate in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs.
Pluristem (WO 16/098061; Applicant’s own work; of record in IDS; hereafter Pluristem-2) is considered relevant prior art for having disclosed culturing placental ASC in 3D culture (e.g. pg 27, “placental ASC-3D”) comprising microcarriers (e.g. pg 13, para 1; pg 16, para 1; pg 18, para 3).
However, Pluristem-2 do not disclose wherein the administered ASCs are administered intranasally, nor yield the phenotypic results of:
reduced neuroinflammation levels in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs; and
reduced extracellular levels of glutamate in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs.
The claims fail to recite, and the specification fails to disclose, a structure/function nexus between the ASC dosage [parameter 3] of the enormous genus of structurally and functionally unrecited and undisclosed ASC cell formularies [parameter 1], and their corresponding ASC functional property(ies) [parameter 2], respectively, administered intranasally to the human subjects [parameter 1] that necessarily and predictably achieves a real-world, clinically meaningful treatment of cocaine addiction in a human subject, and also necessarily and predictably achieves the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs; and/or
reduced extracellular levels of glutamate in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs.
The claims fail to recite, and the specification fails to disclose, a first ASC dosage [parameter 3], e.g. 1x10^5 cells, of the enormous genus of structurally and functionally unrecited and undisclosed ASC cell formularies [parameter 1], e.g. 0.5% fetal ASCs and 80% maternal ASCs, and their corresponding ASC functional property(ies) [parameter 2], e.g. do not differentiate into osteocytes, but are not capable of inhibiting an immune response, respectively, administered intranasally to the human subjects that necessarily and predictably achieves a real-world, clinically meaningful treatment of cocaine addiction in a human subject, but is not able to achieve the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs; and/or
reduced extracellular levels of glutamate in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs, as opposed to
a second ASC dosage [parameter 3], e.g. 1x10^3 cells, of the enormous genus of structurally and functionally unrecited and undisclosed ASC cell formularies [parameter 1], e.g. 15% fetal ASCs and 80% maternal ASCs, and their corresponding ASC functional property(ies) [parameter 2], e.g. do not differentiate into adipocytes and promotes angiogenesis, respectively, administered intranasally to the human subjects that necessarily and predictably achieves a real-world, clinically meaningful treatment of cocaine addiction in a human subject, and is necessarily and predictably able to achieve the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs; and/or
reduced extracellular levels of glutamate in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first ASC dosage [parameter 3], 1x10^7 cells, of the enormous genus of structurally and functionally unrecited and undisclosed ASC cell formularies [parameter 1], e.g. 20% fetal ASCs and 80% maternal ASCs, and their corresponding ASC functional property(ies) [parameter 2], e.g. stimulates T cell proliferation and promotes angiogenesis, respectively, administered intranasally to the human that necessarily and predictably achieves a real-world, clinically meaningful treatment of cocaine addiction in a human subject, but is not able to achieve the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs; and/or
reduced extracellular levels of glutamate in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs, into
a second ASC dosage [parameter 3] of the enormous genus of structurally and functionally unrecited and undisclosed ASC cell formularies [parameter 1], and their corresponding ASC functional property(ies) [parameter 2], respectively, administered intranasally to the human subjects that now necessarily and predictably achieves a real-world, clinically meaningful treatment of cocaine addiction in a human subject and is necessarily and predictably able to achieve the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs; and/or
reduced extracellular levels of glutamate in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs, for example.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that:
an initial pharmaceutical cell composition comprising 1x10^6 structurally [parameter 1] and functionally [parameter 2] undisclosed formulary of ASCs is administered intranasally to a rat subject (Example 13), does not tell you anything at all about:
the enormous genus of structurally different ASC cell formularies comprising 80%-99.9% maternal ASCs of diverse HLA immunophenotypes and/or 10%-20% fetal ASCs of diverse HLA immunophenotypes, e.g. a ratio of 80-90% maternal cells to 10-20% fetal cells (Claims 40-43), for which the independent claim fails to recite an actual ASC cell number dosage, respectively [parameter 1];
their corresponding broad genus of functionally different ASC populations that do not differentiate into adipocytes, do not differentiate into osteocytes, stimulate endothelial cell proliferation, stimulate T cell proliferation, inhibit T cell proliferation, promote angiogenesis, suppress an immune reaction in the subject, and/or promote neurogenesis [parameter 2], respectively;
the enormous genus of ASC cell number dosages and administration regimens, e.g. once as a single dose, or as many as 50 times, weekly or monthly, until the desired response is achieved, whereupon 60% to 99%, or more, of the ASCs are no longer detectable within the subject 4 weeks after administration, to be administered to the human subject, respectively [parameter 3],
so as to necessarily and predictably achieve a real-world, clinically meaningful treatment of cocaine addiction in the human subjects, including necessarily and predictably achieving the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves:
an enormously broad genus of pharmaceutical cell compositions comprising structurally [parameter 1] and functionally [parameter 2] undisclosed formulary of ASCs;
an enormous genus of structurally and functionally different ASC cell formularies comprising 80%-99.9% maternal ASCs of diverse HLA immunophenotypes and/or 10%-20% fetal ASCs of diverse HLA immunophenotypes, e.g. a ratio of 80-90% maternal cells to 10-20% fetal cells (Claims 40-43);
the corresponding broad genus of functionally different ASC populations that do not differentiate into adipocytes, do not differentiate into osteocytes, stimulate endothelial cell proliferation, stimulate T cell proliferation, inhibit T cell proliferation, promote angiogenesis, suppress an immune reaction in the subject, and/or promote neurogenesis [parameter 2], respectively; and
an enormous genus of structurally undisclosed ASC cell dosages, as evidence by the independent claim failing to recite an actual ASC cell number dosage, respectively [parameter 3],
to treat cocaine addiction in the human subjects, including the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the nexus between:
an enormously broad genus of pharmaceutical cell compositions comprising structurally [parameter 1] and functionally [parameter 2] undisclosed formulary of ASCs;
an enormous genus of structurally and functionally different ASC cell formularies comprising 80%-99.9% maternal ASCs of diverse HLA immunophenotypes and/or 10%-20% fetal ASCs of diverse HLA immunophenotypes, e.g. a ratio of 80-90% maternal cells to 10-20% fetal cells (Claims 40-43);
the corresponding broad genus of functionally different ASC populations that do not differentiate into adipocytes, do not differentiate into osteocytes, stimulate endothelial cell proliferation, stimulate T cell proliferation, inhibit T cell proliferation, promote angiogenesis, suppress an immune reaction in the subject, and/or promote neurogenesis [parameter 2], respectively; and
an enormous genus of structurally undisclosed ASC cell dosages, as evidence by the independent claim failing to recite an actual ASC cell number dosage, respectively [parameter 3],
so as to necessarily and predictably achieve a real-world, clinically meaningful treatment of cocaine addiction in the human subjects, including necessarily and predictably achieving the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs, at the time the application was filed.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Response to Arguments
Applicant argues that the specification provides sufficient description of the doses and regimens for intranasal delivery in human subjects.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, the court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
As a second matter, while Example 11 discloses intranasal administration of an ASC composition to rat subjects, the example fails to disclose the structural [parameter 1] and functional [parameter 2] type(s) of ASCs is said composition, nor the ASC dosage [parameter 3] administered to the rat.
While Example 13 discloses intranasal administration of 1x10^6 ASCs [parameter 3] to rat subjects, the example fails to disclose the structural [parameter 1] and functional [parameter 2] type(s) of ASCs is said composition.
The working examples fail to disclose the phenotypic results of:
reduced neuroinflammation levels in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs; and
reduced extracellular levels of glutamate in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs.
Applicant argues that the claimed ASCs must result in treatment of addiction and the specific functional properties of reduced inflammation levels in the nucleus accumbens (NAc) or the ventral tegmental area (VTA) 2 weeks after treatment with the ASCs.
Applicant’s argument(s) has been fully considered, but is not persuasive. As discussed in the rejection, the instant claims are considered to lack adequate written description for failing to recite the dosage of the pharmaceutical composition of ASCs that is to be administered intranasally 1-72 hours, 3-48, and/or 6-24 hours after the subject’s last exposure to the addictive dopamine reuptake inhibitor.
The phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs is dependent upon many different variable parameters, including, but not limited to:
the enormous genus of structurally different ASC cell formularies comprising 60%-99.9% maternal ASCs of diverse HLA immunophenotypes and/or 10%-40% fetal ASCs of diverse HLA immunophenotypes, e.g. a ratio of 60-90% maternal cells to 10-40% fetal cells (Claims 40-43), respectively [parameter 1];
their corresponding broad genus of functionally different ASC populations that do not differentiate into adipocytes, do not differentiate into osteocytes, stimulate endothelial cell proliferation, stimulate T cell proliferation, inhibit T cell proliferation, promote angiogenesis, suppress an immune reaction in the subject, and/or promote neurogenesis [parameter 2], respectively;
an enormous genus of ASC cell number dosages and administration regimens, e.g. once as a single dose, or as many as 50 times, weekly or monthly, until the desired response is achieved, whereupon 60% to 99%, or more, of the ASCs are no longer detectable within the subject 4 weeks after administration, respectively [parameter 3]; and
to thereby treat an enormous genus of addicting substances, including, but not limited to cocaine, methamphetamine, methylhenidate, “ecstasy”, phenylethylamine, dexamphetamine, phentermine, opiates, opiods, alcohol, barbiturates, tranquilizers, benzodiazepines, cannabis, GHB, heroin, morpine, codein, methadone, buprenorphine, pethidine, dilaudid, kapanol, hallucinogens, psychedelic compounds such as DMT, ayahuasca, psilocybin, mescaline, LSD, dissociative compounds such as ketamine, MXE, PCP, and DXM, or deliriants such as deadly nightshade, Angel’s Trumpet, Jimson week, henbane, mandrake, and nutmeg, respectively [parameter 4].
The claim(s) denote that there is an amount of the ASC pharmaceutical composition that, upon administration to the subject, is not, in fact, a therapeutically effective amount sufficient to necessarily and predictably achieve the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
3. Claims 1, 3-4, 8-9, 34-35, 40, and 42-43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejections.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that:
an initial pharmaceutical cell composition comprising 1x10^6 structurally [parameter 1] and functionally [parameter 2] undisclosed formulary of ASCs is administered intranasally to a rat subject (Example 13), does not tell you anything at all about:
the enormous genus of structurally different ASC cell formularies comprising 80%-99.9% maternal ASCs of diverse HLA immunophenotypes and/or 10%-20% fetal ASCs of diverse HLA immunophenotypes, e.g. a ratio of 80-90% maternal cells to 10-20% fetal cells (Claims 40-43), for which the independent claim fails to recite an actual ASC cell number dosage, respectively [parameter 1];
their corresponding broad genus of functionally different ASC populations that do not differentiate into adipocytes, do not differentiate into osteocytes, stimulate endothelial cell proliferation, stimulate T cell proliferation, inhibit T cell proliferation, promote angiogenesis, suppress an immune reaction in the subject, and/or promote neurogenesis [parameter 2], respectively;
the enormous genus of ASC cell number dosages and administration regimens, e.g. once as a single dose, or as many as 50 times, weekly or monthly, until the desired response is achieved, whereupon 60% to 99%, or more, of the ASCs are no longer detectable within the subject 4 weeks after administration, to be administered to the human subject, respectively [parameter 3],
so as to necessarily and predictably achieve a real-world, clinically meaningful treatment of cocaine addiction in the human subjects, including necessarily and predictably achieving the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves:
an enormously broad genus of pharmaceutical cell compositions comprising structurally [parameter 1] and functionally [parameter 2] undisclosed formulary of ASCs;
an enormous genus of structurally and functionally different ASC cell formularies comprising 80%-99.9% maternal ASCs of diverse HLA immunophenotypes and/or 10%-20% fetal ASCs of diverse HLA immunophenotypes, e.g. a ratio of 80-90% maternal cells to 10-20% fetal cells (Claims 40-43);
the corresponding broad genus of functionally different ASC populations that do not differentiate into adipocytes, do not differentiate into osteocytes, stimulate endothelial cell proliferation, stimulate T cell proliferation, inhibit T cell proliferation, promote angiogenesis, suppress an immune reaction in the subject, and/or promote neurogenesis [parameter 2], respectively; and
an enormous genus of structurally undisclosed ASC cell dosages, as evidence by the independent claim failing to recite an actual ASC cell number dosage, respectively [parameter 3],
to treat cocaine addiction in the human subjects, including the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the nexus between:
an enormously broad genus of pharmaceutical cell compositions comprising structurally [parameter 1] and functionally [parameter 2] undisclosed formulary of ASCs;
an enormous genus of structurally and functionally different ASC cell formularies comprising 80%-99.9% maternal ASCs of diverse HLA immunophenotypes and/or 10%-20% fetal ASCs of diverse HLA immunophenotypes, e.g. a ratio of 80-90% maternal cells to 10-20% fetal cells (Claims 40-43);
the corresponding broad genus of functionally different ASC populations that do not differentiate into adipocytes, do not differentiate into osteocytes, stimulate endothelial cell proliferation, stimulate T cell proliferation, inhibit T cell proliferation, promote angiogenesis, suppress an immune reaction in the subject, and/or promote neurogenesis [parameter 2], respectively; and
an enormous genus of structurally undisclosed ASC cell dosages, as evidence by the independent claim failing to recite an actual ASC cell number dosage, respectively [parameter 3],
so as to necessarily and predictably achieve a real-world, clinically meaningful treatment of cocaine addiction in the human subjects, including necessarily and predictably achieving the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs, at the time the application was filed.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Mingozzi and High (Immune responses to AAV vectors: overcoming barriers to successful gene therapy, Blood 122(1): 23-36, 2013) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Perrin (Make Mouse Studies Work, Nature (507): 423-425, 2014) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1).
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023) is considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of nor enabling the nexus between:
the enormous genus of structurally different ASC cell formularies comprising 80%-99.9% maternal ASCs of diverse HLA immunophenotypes and/or 30%-99.9% fetal ASCs of diverse HLA immunophenotypes, e.g. a ratio of 20-90% maternal cells to 20-90% fetal cells, respectively [parameter 1];
their corresponding broad genus of functionally different ASC populations that do not differentiate into adipocytes, do not differentiate into osteocytes, stimulate endothelial cell proliferation, stimulate T cell proliferation, inhibit T cell proliferation, promote angiogenesis, suppress an immune reaction in the subject, and/or promote neurogenesis [parameter 2], respectively;
the enormous genus of ASC cell number dosages and administration regimens, e.g. once as a single dose, or as many as 50 times, weekly or monthly, until the desired response is achieved, whereupon 60% to 99%, or more, of the ASCs are no longer detectable within the subject 4 weeks after administration, respectively [parameter 3];
to thereby treat an enormous genus of addicting substances, including, but not limited to cocaine, methamphetamine, methylhenidate, “ecstasy”, phenylethylamine, dexamphetamine, phentermine, opiates, opiods, alcohol, barbiturates, tranquilizers, benzodiazepines, cannabis, GHB, heroin, morpine, codein, methadone, buprenorphine, pethidine, dilaudid, kapanol, hallucinogens, psychedelic compounds such as DMT, ayahuasca, psilocybin, mescaline, LSD, dissociative compounds such as ketamine, MXE, PCP, and DXM, or deliriants such as deadly nightshade, Angel’s Trumpet, Jimson week, henbane, mandrake, and nutmeg, respectively [parameter 4],
in human subjects,
so as to necessarily and predictably achieve a real-world, clinically meaningful treatment of addiction in the human subjects, including necessarily and predictably achieving the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2, 4, and/or 6 weeks after treatment with the ASCs, at the time the application was filed.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Response to Arguments
Applicant argues that cited prior art Mingozzi et al, Greenberg et al, and Maguire et al are directed to AAV viral vectors, not ASC cell therapy.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Mingozzi demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Greenberg taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage. There is an art-recognized unpredictability translating pre-clinical animal model results into human clinical therapies, and that required early phase developmental studies are both complex and costly.
Maguire et al, like Greenberg, taught that there are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic, e.g. species-related physiological differences between mice and humans.
Perrin taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Tobias taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
Applicant argues that the artisan would be able to determine an appropriate dosage and dosing regimen for intranasal delivery.
Applicant’s argument(s) has been fully considered, but is not persuasive.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves:
the enormous genus of structurally different ASC cell formularies comprising 60%-99.9% maternal ASCs of diverse HLA immunophenotypes and/or 10%-40% fetal ASCs of diverse HLA immunophenotypes, e.g. a ratio of 60-90% maternal cells to 10-40% fetal cells (Claims 40-43), respectively [parameter 1];
their corresponding broad genus of functionally different ASC populations that do not differentiate into adipocytes, do not differentiate into osteocytes, stimulate endothelial cell proliferation, stimulate T cell proliferation, inhibit T cell proliferation, promote angiogenesis, suppress an immune reaction in the subject, and/or promote neurogenesis [parameter 2], respectively;
an enormous genus of ASC cell number dosages and administration regimens, e.g. once as a single dose, or as many as 50 times, weekly or monthly, until the desired response is achieved, whereupon 60% to 99%, or more, of the ASCs are no longer detectable within the subject 4 weeks after administration, respectively [parameter 3];
to thereby treat an enormous genus of addicting substances, including, but not limited to cocaine, methamphetamine, methylhenidate, “ecstasy”, phenylethylamine, dexamphetamine, phentermine, opiates, opiods, alcohol, barbiturates, tranquilizers, benzodiazepines, cannabis, GHB, heroin, morpine, codein, methadone, buprenorphine, pethidine, dilaudid, kapanol, hallucinogens, psychedelic compounds such as DMT, ayahuasca, psilocybin, mescaline, LSD, dissociative compounds such as ketamine, MXE, PCP, and DXM, or deliriants such as deadly nightshade, Angel’s Trumpet, Jimson week, henbane, mandrake, and nutmeg, respectively [parameter 4],
in human subjects.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Applicant argues that methods for measuring neuro-inflammation were known in the art at the time of filing. Moreover, Example 13 provides a general guideline for measuring neuroinflammation in rats treated with ASCs.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Knowing that an initial pharmaceutical cell composition comprising 1x10^6 structurally [parameter 1] and functionally [parameter 2] undisclosed formulary of ASCs administered intranasally to a rat subject (Example 13), does not tell you anything at all about:
the enormous genus of structurally different ASC cell formularies comprising 60%-99.9% maternal ASCs of diverse HLA immunophenotypes and/or 10%-40% fetal ASCs of diverse HLA immunophenotypes, e.g. a ratio of 60-90% maternal cells to 10-40% fetal cells (Claims 40-43), respectively [parameter 1];
their corresponding broad genus of functionally different ASC populations that do not differentiate into adipocytes, do not differentiate into osteocytes, stimulate endothelial cell proliferation, stimulate T cell proliferation, inhibit T cell proliferation, promote angiogenesis, suppress an immune reaction in the subject, and/or promote neurogenesis [parameter 2], respectively;
the enormous genus of ASC cell number dosages and administration regimens, e.g. once as a single dose, or as many as 50 times, weekly or monthly, until the desired response is achieved, whereupon 60% to 99%, or more, of the ASCs are no longer detectable within the subject 4 weeks after administration, respectively [parameter 3]; and
the enormous genus of addicting substances, including, but not limited to cocaine, methamphetamine, methylhenidate, “ecstasy”, phenylethylamine, dexamphetamine, phentermine, opiates, opiods, alcohol, barbiturates, tranquilizers, benzodiazepines, cannabis, GHB, heroin, morpine, codein, methadone, buprenorphine, pethidine, dilaudid, kapanol, hallucinogens, psychedelic compounds such as DMT, ayahuasca, psilocybin, mescaline, LSD, dissociative compounds such as ketamine, MXE, PCP, and DXM, or deliriants such as deadly nightshade, Angel’s Trumpet, Jimson week, henbane, mandrake, and nutmeg, respectively [parameter 4],
so as to necessarily and predictably achieve a real-world, clinically meaningful treatment of addiction in the human subjects, including necessarily and predictably achieving the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs.
Applicant argues that the skilled artisan would not be subject to undue experimentation to make and use the claimed method.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
Those of ordinary skill in the art recognize that:
i) lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans (Mingozzi et al);
ii) there are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic, e.g. species-related physiological differences between mice and humans (Maguire et al);
iii) the odds of an experimental treatment making it from mouse or monkey to human are very low, e.g. less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval, such that it is no wonder some researchers joke about mice and monkeys lying and exaggerating (Tobias et al);
iv) despite success in experimental animal models, translating pharmaceutical dosage strategies from the laboratory to the clinic remains at an early stage, whereby experience indicates that there is a need to carefully consider the dose; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (Greenberg); and
v) the series of clinical trials for a potential therapy can cost hundreds of millions of dollars and the human costs are even greater, because experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments, and financial resources for clinical trials are being wasted and [human] lives are being lost. Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. Even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (Perrin et al).
Applicant argues that a therapeutically effective amount or dose can be estimated initially from in vitro and cell culture assays.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant fails to point with particularity where the specification discloses a working example of an ASC dosage determined from some hypothetical, straw-man argument of in vitro cell culture assays so as to necessarily and predictably achieve “therapeutically effective amount” of:
the enormous genus of structurally different ASC cell formularies comprising 60%-99.9% maternal ASCs of diverse HLA immunophenotypes and/or 10%-40% fetal ASCs of diverse HLA immunophenotypes, e.g. a ratio of 60-90% maternal cells to 10-40% fetal cells (Claims 40-43), respectively [parameter 1];
their corresponding broad genus of functionally different ASC populations that do not differentiate into adipocytes, do not differentiate into osteocytes, stimulate endothelial cell proliferation, stimulate T cell proliferation, inhibit T cell proliferation, promote angiogenesis, suppress an immune reaction in the subject, and/or promote neurogenesis [parameter 2], respectively;
the enormous genus of ASC cell number dosages and administration regimens, e.g. once as a single dose, or as many as 50 times, weekly or monthly, until the desired response is achieved, whereupon 60% to 99%, or more, of the ASCs are no longer detectable within the subject 4 weeks after administration, respectively [parameter 3]; and
the enormous genus of addicting substances, including, but not limited to cocaine, methamphetamine, methylhenidate, “ecstasy”, phenylethylamine, dexamphetamine, phentermine, opiates, opiods, alcohol, barbiturates, tranquilizers, benzodiazepines, cannabis, GHB, heroin, morpine, codein, methadone, buprenorphine, pethidine, dilaudid, kapanol, hallucinogens, psychedelic compounds such as DMT, ayahuasca, psilocybin, mescaline, LSD, dissociative compounds such as ketamine, MXE, PCP, and DXM, or deliriants such as deadly nightshade, Angel’s Trumpet, Jimson week, henbane, mandrake, and nutmeg, respectively [parameter 4],
so as to necessarily and predictably achieve a real-world, clinically meaningful treatment of addiction in the human subjects, including necessarily and predictably achieving the phenotypic functional properties of:
reduced neuroinflammation levels in the NAc or the VTA 2 weeks after treatment with the ASCs.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
Conclusion
4. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638