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 September 22, 2025.
Amendments
Applicant's amendments, filed September 22, 2025, is acknowledged. Applicant has cancelled Claims 1-267, and amended Claims 277 and 297-299.
Claims 268-299 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group II, Claim(s) 268-298, drawn to a method of treating a patient, the method comprising the step(s) of:
a) administering to said patient a first population of hypoimmunogenic cells;
b) performing a detection assay on said patient after step (a); and
c) administering to said patient a second population of hypoimmunogenic cells.
Within Group II, Applicant has elected the following species, wherein:
i) the alternative first and second hypoimmunogenic cell species, respectively, comprise the same cell type, as recited in Claim 285;
ii) alternative genomic modification species is reduced expression of B2M and CIITA, and increased expression of CD47, as recited in Claims 282-284 and 297;
iii) the alternative systemic immune response is a reduced level of immune activation or no immune activation in the patient, as recited in Claims 269;
iv) the alternative patient treatment regimen is the patient is not administered an immunosuppressive agent at least 2 or more days after administration of the first population of cells, as recited in Claim 277(a); and
v) the alternative disease/disorder is lupus, as recited in Claims 294.
Claims 268-299 are pending.
Claims 270-274, 278, 280, 286-293, 295-296, and 298-299 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 268-269, 275-277, 279, 281-285, 294, and 297 are under consideration.
Priority
This application is a 371 of PCT/US2021/029443 filed on April 27, 2021. Applicant’s claim for the benefit of a prior-filed application provisional application 63/052,360 filed on July 15, 2020 and 63/016,190 filed on April 27, 2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on December 4, 2023 that has been considered.
The information disclosure statement filed December 4, 2023 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Claim Objections
1. The prior objection to Claims 277, and 297-299 are withdrawn in light of Applicant’s amendment to the claims.
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.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
2. Claims 268-269, 275-277, 279, 281-285, 294, and 297 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claims 268 and 297 recite the broad recitation “…at least…” and the claim also recites “based….on” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
There are two limitations in the phrase “based at least on”: “based on” and “at least”.
The phrase “at least” refers to additional, presently unrecited parameters, upon which a therapeutically effective amount of a second population of cells is to be determined and thus-administered to the patient.
Performing step (c) administering… based on detecting the absence of a systemic immune response in the patient elicited by the first population of hypoimmunogenic cells does not fulfill the additional, presently unrecited parameters, upon which a therapeutically effective amount of a second population of cells is to be determined and thus-administered to the patient.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
3. Claims 268-269, 275-277, 279, 281-285, 294, and 297 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999).
The term “patient” in Claims 268 and 297 is used by the claim to mean “human or non-human animal subject”, while the accepted meaning is “human”.
The specification discloses “patient or subject” [00275], “patient (e.g. recipient subject”) [00278], and “patient, e.g. human patient” [00406], whereby [00200] discloses the “subject” includes human and non-human animals such as fish, amphibians, lizards, and mammals.
The specification working example (Example 1, [00470]) discloses a non-human primate animal model.
The term “patient” is indefinite because the specification does not clearly redefine the term.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Applicant should amend the claim to recite ‘human patient’.
Alternatively, Applicant should amend the claim to cancel “patient”, and instead recite ‘subject’.
4. Claim 275 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “recovery period” in Claim 275 is a relative term which renders the claim indefinite. The term “recovery period” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. See, instead, Claim 276.
5. Claim 275 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, Claim 275 recites the broad recitation “, or 60 months or more”, and the claim also recites “at least 3 days” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
There is no upper limit to the recovery period, per the ultimate limitation, “or more”.
At least 3 days fails to achieve the broader recitation, “60 months or more”, for example.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
6. Claims 277 and 279 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, Claims 277 and 279 recite the broad recitation “or more days”, and the claim also recites “at least 2” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
There is no upper limit to the period of time in which the immunosuppressive agent is not administered, per the ultimate limitation, “or more days”.
At least 2 days fails to achieve the broader recitation, “or more days”, for example.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
7. Claim 281 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 268 recites a cell that has been genetically modified to inactivate or disrupt one or more MHC-I and/or MHC-II alleles.
Claim 281 recites wherein the genetic modification to inactivate or disrupt one or more MHC-I and/or MHC-II alleles results in the functional properties of:
a) reduces expression of MHC-I and/or MHC-II;
b) reduces cell surface protein expression of MHC-I and/or MHC-II; and/or
c) reduces cells surface trafficking of MHC-I and/or MHC-II.
Either these are inherent properties of (that naturally flow from) the genetic modification to inactivate or disrupt the MHC-I and/or MHC-II alleles, respectively, or they are not, and something [structure] of the genetic modification(s) of independent Claim 268 must change.
To the extent they are inherent properties of (that naturally flow from) the genetic modification(s) of the independent claim, then the instant claim fails to further limit the independent claim.
Furthermore, in regard to instant claims, it is noted that the “wherein….” clause does not recite any additional structure(s) and/or active method step(s), but simply states a characterization or conclusion of the results of genetic modification(s) positively recited. Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
The claims fail to recite, and the specification fails to disclose, genetic modification(s) that inactivate and/or disrupt the MHC-I and/or MHC-II alleles, respectively, that do not also achieve the functional properties recited in Claim 281.
'Even if such a phrase did hold patentable weight, the phrase would likely be rejected under 35 USC 112(b) for being indefinite because such a phrase would amount to a 'functional limitation' whereby one of ordinary skill in the art would essentially need to 'guess' what steps must occur in the claim, in addition to the positively-recited method steps, in order to result in 'wherein the....' (the 'intended result' phrase in the claim).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
8. Claim(s) 281 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 268 recites a cell that has been genetically modified to inactivate or disrupt one or more MHC-I and/or MHC-II alleles.
Claim 281 recites wherein the genetic modification to inactivate or disrupt one or more MHC-I and/or MHC-II alleles results in the functional properties of:
a) reduces expression of MHC-I and/or MHC-II;
b) reduces cell surface protein expression of MHC-I and/or MHC-II; and/or
c) reduces cells surface trafficking of MHC-I and/or MHC-II.
Either these are inherent properties of (that naturally flow from) the genetic modification to inactivate or disrupt the MHC-I and/or MHC-II alleles, respectively, or they are not, and something [structure] of the genetic modification(s) of independent Claim 268 must change.
The claim denotes that not all of the structures/method steps of the independent claim are able to achieve the functional property(ies) recited in the dependent claim(s).
To the extent they are not inherent properties of (that naturally flow from) the genetic modification(s) of the independent claim, then the instant claim is considered to lack adequate written description for failing to recite the structure(s) and/or method step(s) that is/are necessary and sufficient to cause the recited functional language.
The “wherein…” clause merely states functional characteristic(s) without providing any indication about how the functional characteristic(s) is/are provided. The functional characteristic(s) do/does not follow from (is not an inherent property of) the structure(s) recited in the independent claim. The specification fails to disclose what structural changes to the genetic modification(s) is/are necessary and sufficient to cause the recited function(s) and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
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 claims fail to recite, and the specification fails to disclose, genetic modification(s) that inactivate and/or disrupt the MHC-I and/or MHC-II alleles, respectively, that do not also achieve the functional properties recited in Claim 281.
The claims fail to recite, and the specification fails to disclose, genetic modifications that inactivate or disrupt one or more MHC-I and/or MHC-II alleles that do NOT achieve the functional properties of:
a) reduces expression of MHC-I and/or MHC-II;
b) reduces cell surface protein expression of MHC-I and/or MHC-II; and/or
c) reduces cells surface trafficking of MHC-I and/or MHC-II, as opposed to
genetic modifications that inactivate or disrupt one or more MHC-I and/or MHC-II alleles that necessarily and predictably achieve the functional properties of:
a) reduces expression of MHC-I and/or MHC-II;
b) reduces cell surface protein expression of MHC-I and/or MHC-II; and/or
c) reduces cells surface trafficking of MHC-I and/or MHC-II.
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”).
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 broad genus of genetic modifications recited at a high level of generality that inactivate or disrupt one or more MHC-I and/or MHC-II alleles that do NOT achieve the functional properties of:
a) reduces expression of MHC-I and/or MHC-II;
b) reduces cell surface protein expression of MHC-I and/or MHC-II; and/or
c) reduces cells surface trafficking of MHC-I and/or MHC-II, in addition to
the broad genus of genetic modifications recited at a high level of generality that inactivate or disrupt one or more MHC-I and/or MHC-II alleles that necessarily and predictably achieve the functional properties of:
a) reduces expression of MHC-I and/or MHC-II;
b) reduces cell surface protein expression of MHC-I and/or MHC-II; and/or
c) reduces cells surface trafficking of MHC-I and/or MHC-II,
at the time the application was filed.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language.
9. Claims 268-269, 275-277, 279, 281-285, 294, and 297 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 268 and 297 recite the limitation, “absence of a systemic immune response”.
English has two articles: ‘the’, and ‘a/an’.
‘the’ is a definite article, referring to a specific or particular noun; whereas, ‘a/an’ is an indefinite article, modifying non-specific or non-particular nouns.
The recitation implies a genus of undisclosed systemic immune responses by which “absence of” is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The specification discloses systemic immune responses may include, but are not limited to:
reduced or no immune activation in the patient [0018];
reduced or no TH1 activation in the patient [0018];
reduced or no PBMC activation in the patient [0018];
reduced or no donor-specific IgG antibodies in the patient [0018];
reduced or no IgM and IgG antibody production in the patient [0018];
reduced or no cytotoxic T cell killing in the patient [0018];
reduced or no immune activation in the patient [0018];
are not susceptible to NK cell-mediated lysis [00172]; and/or
are not susceptible to macrophage engulfment [00172].
Beggs et al (Immunologic Consequences of Multiple, High-Dose Administration of Allogeneic Mesenchymal Stem Cells to Baboons, Cell Transplantation 15: 711-721, 2006) is considered relevant prior art for having taught a method of transplanting hypoimmunogenic MSCs into a baboon patient (e.g. Abstract, “[MSCs] express low immunogenicity; pg 711, Introduction, col. 2, “These cells do not express….MHC class II”), the method comprising the step(s) of:
i) administering to the baboon patient a first population of allogeneic baboon MSCs;
ii) detecting one or more immune responses in the baboon patient elicited by the first population of MSCs, e.g. mitogen responsiveness, PBMC phenotyping, IgG and IgM immunoglobulin levels, mixed lymphocyte reaction, and T-cell reactivity to donor alloantigens (e.g. pg 712, col. 1; pg 714, col. 2; pg 715, col.s 1-2); and
iii) administering to the baboon patient a second population of allogeneic baboon MSCs (e.g. Abstract; Figure 1).
Beggs et al taught that the hypoimmunogenic, allogeneic baboon MSCs did not affect the overall (syn. systemic) immune system, nor cause any apparent health problems (e.g. pgs 717-718, joining para), even though some animals developed variable alloantigen antibodies (e.g. pg 716, col. 2; Table 2), or generated a higher percentage of CD3+, CD4+ cells and a lower percentage of CD3+, CD8+ cells in the PBMCs (e.g. pg 717, col. 1).
If there are multiple ways to measure “absence of a systemic immune response”, to wit, phenotypic result, yet each systemic immune response assay yields a different result, then the claim may be indefinite because it is unclear which method is to be performed to determine infringement.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language.
10. Claims 268-269, 275-277, 279, 281-285, 294, and 297 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 268 and 297 recite a second population of hypoimmunogenic cells.
The term “hypoimmunogenic” is a relative term which renders the claim indefinite. The term “hypoimmunogenic” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The claimed cells are recited at a high level of generality.
The recitation implies a genus of undisclosed phenotypes by which “hypoimmunogenic” is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The specification discloses “hypoimmunogenic” may include, but are not limited to:
elicits reduced or no immune activation in the patient [0018];
elicits reduced or no TH1 activation in the patient [0018];
elicits reduced or no PBMC activation in the patient [0018];
elicits reduced or no donor-specific IgG antibodies in the patient [0018];
elicits reduced or no IgM and IgG antibody production in the patient [0018];
elicits reduced or no cytotoxic T cell killing in the patient [0018];
elicits reduced or no immune activation in the patient [0018];
are not susceptible to NK cell-mediated lysis [00172];
are not susceptible to macrophage engulfment [00172];
have reduced immunogenicity, by however small degree, or as much as 99% less immunogenicity relative to a non-hypoimmunogenic cell [00174, 176]; and/or
less prone to immune rejection, by however small degree, or as much as 99% less immunogenicity relative to a non-hypoimmunogenic cell [00176].
If there are multiple ways to measure “hypoimmunogenic”, to wit, different immunological properties and/or phenotypes, yet each yields a different result, then the claim may be indefinite because it is unclear which method is to be performed to determine infringement.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language.
When functional claim language is found indefinite, it typically lacks an adequate written description under §112(a), because an indefinite, unbounded functional limitation would cover a plurality of undisclosed structures and/or method steps of performing a function and indicate that the inventor has not provided sufficient disclosure to show possession of the invention. Thus, in most cases, a §112(b) rejection that is based on functional language having unclear (or no) claim boundaries should be accompanied by a rejection under §112(a) based on failure to provide a written description for the claim. See MPEP 2173.05(g).
11. Claims 268-269, 275-277, 279, 281-285, 294, and 297 are rejected 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.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
Claims 268 and 297 recite a second population of hypoimmunogenic cells.
The term “hypoimmunogenic” is a relative term which renders the claim indefinite. The term “hypoimmunogenic” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The claimed cells are recited at a high level of generality.
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).
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’).
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 clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language.
12. Claims 268-269, 275-277, 279, 281-285, 294, and 297 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 268 and 297 recite the step(s) of:
a) administering to a patient a therapeutically effective amount of a first cell population; and
c) administering to a patient a therapeutically effective amount of a second cell population.
Therapeutically effective amount to do what??
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the first and/or second population of cells that, upon administration to the subject, is not, in fact, “a therapeutically effective amount”.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human or non-human animal to be treated [parameter 1];
the type of first and second population of cells, respectively [parameter 2];
the administration route(s) of the first and second population of cells, respectively [parameter 3];
the cell dosage(s) of the first and second population of cells, respectively [parameter 4];
the disease/disorder/condition to be treated [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
Parameter 1
The claims are broad for reasonably encompassing an enormous genus of human and non-human animals [00200].
The claims are broad for encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
Parameter 2
The claims are broad for reasonably encompassing an enormous genus of anatomically and physiologically different cell types including, but not limited to, pluripotent stem cell, embryonic stem cell, T cell, neuron, glial cells, astrocytes, oligodendrocytes, hepatocyte, cardiomyocyte, endothelial cell, thyroid cell, pancreatic islet cell, beta cell, retinal pigment epithelial cell (e.g. [00179, 206-207, 419]) in the first and second populations.
The art recognizes that there are at least 1,000 different types of cells in the human body (List of distinct cell types in the adult human body, en.wikipedia.org/wiki; last accessed June 13, 2024).
Parameter 3
While the specification discloses administration routes such as intravenous, intra-arterial, intracoronary, intramuscular, intraperitoneal, intra-abdominal, intraocular, retrobulbar, subcutaneous, intraspinal, intracerebroventricular, or intrathecal [00392, 426], the claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic.
The specification discloses the cells may be administered by any appropriate route which results in delivery to a desired location [00181].
Parameter 4
The claimed methods are recited at a high level of generality for the first and second cell population dosages that is/are to be administered, including, but not limited to, as little as 10 to 1x10^20 cells.
The specification is silent to the first and second cell population dosages.
At best, Example 1 [00470-471] discloses administering a first and second population of about 1x10^7 human cells whose genomes have been genetically modified to knockout the endogenous B2M, CIITA genes (B2M-/-, CIITA-/-) and to further comprise a CD47 transgene, thereby increasing expression of CD47, to a non-human primate.
Parameter 5
The claims are broad for reasonably encompassing an enormous genus of etiologically and pathologically distinct diseases, disorders, or conditions, recited at a high level of generality, including, but not limited to, the genus recited in Claim 294, and as disclosed in [00183] (genus of cancers), [00184] (genus of infectious diseases), [00185] (genus of autoimmune diseases), [00229] (genus of autoimmune or inflammatory disorders), [00380] (genus of cardiac disorders), [00398, 406] (genus of neurological disorders), [00435] (genus of vascular disorders), and [00461] (genus of ocular disorders).
Parameter 6
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective amount is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
[00260] discloses that any positive therapeutic indication can be indicative of a response to treatment, whereby “any positive…indication” is an arbitrary and subjective determination.
[00262] discloses a minimal reduction of tumor size, whereby “minimal” is an arbitrary and subjective determination.
[00263] discloses a minimal change in tumor growth rate, whereby “minimal” is an arbitrary and subjective determination.
[00264] discloses a minimal reduction in metastasis and/or metastatic progression, whereby “minimal” is an arbitrary and subjective determination.
[00272, 381] discloses to treat, reduce, ameliorate, diminish, or slow, one or more symptoms of a disease state, whereby “reduce”, “ameliorate”, “diminish”, and/or “slow” is/are an arbitrary and subjective determination.
[00273] discloses a minimal restoration of loss of function, whereby “minimal” is an arbitrary and subjective determination.
The specification discloses the cells may be administered by any appropriate route which results in delivery to a desired location, whereby the viability of the administered cells may be as short as a few hours [00181].
What is/are the therapeutic purpose(s) of the cells if they die within 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours after administration to the patient???
What is their therapeutic achievement?
If there are multiple ways to measure “therapeutically effective amount”, to wit, concentration, time after administration, and/or phenotypic result, yet each yields a different result, then the claim may be indefinite because it is unclear which method is to be performed to determine infringement.
The claims fail to recite, and the specification fails to disclose, a first hypoimmunogenic cell population dosage administered via a first administration route, e.g. subcutaneously, that is necessarily and predictably able to slow blindness in a subject, as opposed a second hypoimmunogenic cell population dosage administered via a second administration route, e.g. intravenously, that is unable to ameliorate macular degeneration in a subject, for example.
The claims fail to recite, and the specification fails to disclose, a first hypoimmunogenic cell population dosage administered via a first administration route, e.g. intramuscularly, that is necessarily and predictably able to decrease metastasis in a subject, but is unable to slow tumor growth rate in a subject, for example.
The claims fail to recite, and the specification fails to disclose what modification(s) to a first hypoimmunogenic cell population dosage administered via a first administration route, e.g. via intrathecal injection, that is unable to reduce complications associated with Parkinson’s disease, transforms said first hypoimmunogenic cell population dosage and/or first administration route into one that is now necessarily and predictably capable of reducing complications associated with Parkinson’s disease.
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, whereby the therapeutically effective amount of the first and second hypoimmunogenic cell population dosages administered is/are a result-effective variable dependent upon many different parameters, thereby rendering the claim indefinite.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Appropriate correction is required.
13. Claims 268-269, 275-277, 279, 281-285, 294, and 297 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.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
Claims 268 and 297 recite the step(s) of:
a) administering to a patient a therapeutically effective amount of a first cell population; and
c) administering to a patient a therapeutically effective amount of a second cell population.
Therapeutically effective amount to do what??
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the first and/or second population of cells that, upon administration to the subject, is not, in fact, “a therapeutically effective amount”.
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 phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human or non-human animal to be treated [parameter 1];
the type of first and second population of cells, respectively [parameter 2];
the administration route(s) of the first and second population of cells, respectively [parameter 3];
the cell dosage(s) of the first and second population of cells, respectively [parameter 4];
the disease/disorder/condition to be treated [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
The specification discloses the cells may be administered by any appropriate route which results in delivery to a desired location, whereby the viability of the administered cells may be as short as a few hours [00181].
What is/are the therapeutic purpose(s) of the cells if they die within 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours after administration to the patient???
What is their therapeutic achievement?
The claims fail to recite, and the specification fails to disclose, a first hypoimmunogenic cell population dosage administered via a first administration route, e.g. subcutaneously, that is necessarily and predictably able to slow blindness in a subject, as opposed a second hypoimmunogenic cell population dosage administered via a second administration route, e.g. intravenously, that is unable to ameliorate macular degeneration in a subject, for example.
The claims fail to recite, and the specification fails to disclose, a first hypoimmunogenic cell population dosage administered via a first administration route, e.g. intramuscularly, that is necessarily and predictably able to decrease metastasis in a subject, but is unable to slow tumor growth rate in a subject, for example.
The claims fail to recite, and the specification fails to disclose what modification(s) to