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 March 31, 2026.
Amendments
Applicant's amendments, filed March 31, 2026, is acknowledged. Applicant has cancelled Claims 1-267, 269, 281, and 284-285, amended Claims 268, 276-277, 279, and 297, and withdrawn Claims 270-274, 278, 280, 286-293, 295-296, and 298-299.
Claims 268, 270-280, 282-283, and 286-299 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, 270-280, 282-283, and 286-299 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Claims 270-274, 278, 280, 286-293, 295-296, and 298-299 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.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, 275-277, 279, 282-283, 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 March 31, 2026 that has been considered.
The information disclosure statement filed March 31, 2026 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 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.
1. The prior rejection of Claims 268-269, 275-277, 279, 281-285, 294, and 297 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendments to the independent claims cancelling “at least”, which the Examiner finds persuasive.
2. The prior rejection of Claims 268-269, 275-277, 279, 281-285, 294, and 297 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendments to the claims cancelling “patient”, which the Examiner finds persuasive.
3. The prior rejection of Claim 276 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendments to the claim, which the Examiner finds persuasive.
4. The prior rejection of Claims 277 and 279 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendments to the claim cancelling “at least”, which the Examiner finds persuasive.
5. The prior rejections of Claim 281 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, and under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, are withdrawn in light of Applicant’s cancellation of the claim.
6. The prior rejections of Claims 268-269, 275-277, 279, 281-285, 294, and 297 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, are withdrawn in light of Applicant’s amendments to the claims cancelling recitation of “hypoimmunogenic”, and instead recited “engineered”, which the Examiner finds persuasive.
7. The prior rejection of Claim 275 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s argument that [00211] discloses the recovery period to be the period of time in which the subject is not administered hypoimmungenic cells, which the Examiner finds persuasive.
8. The prior rejection of Claims 268-269, 275-277, 279, 281-285, and 294 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s cancellation of the limitation, “absence of a systemic immune response”, and instead recited “a reduced level of immune activation or no immune activation”, which the Examiner finds persuasive.
9. The prior rejection of Claims 268-269, 275-277, 279, 281-283, 285, and 294 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s cancellation of “tolerogenic factor” in the independent claim, and instead recited CD47, which the Examiner finds persuasive.
10. Claim 275 stands 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 method of treating a subject comprising the steps of:
administering to the subject a first population of engineered cells;
detecting an immune response elicited by said first population of cells; and
administering to the subject a second population of engineered cells.
Claim 275, dependent upon Claim 268, recites wherein the method comprises a recovery period between steps (a) and (c). As discussed above, Applicant argues that [00211] discloses the recovery period to be the period of time in which the subject is not administered the engineered hypoimmungenic cells.
Thus, Claim 275 fails to further limit the independent claim because it is axiomatic that there is a period of time between steps (a) and (c) in which no cells are administered to the subject (syn. recovery period, per Applicant’s [00211] definition), to wit, between steps (a) and (b) and/or steps (b) and (c).
The specification fails to disclose wherein the step (a) administration is performed concurrently with step (b) detecting and/or step (c) administration, that is to say, there is no period of time in which the subject is not experiencing administration of the first population of cells (syn. continuous administration).
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.
Response to Amendment
Claim 275 continues to suffer from failing to further limit the independent claim because it is axiomatic that there is a period of time between steps (a) and (c) in which no cells are administered to the subject (syn. recovery period, per Applicant’s [00211] definition), to wit, between steps (a) and (b) and/or steps (b) and (c).
The Examiner suggests, for example:
i) cancelling Claim 275, and amending Claim 276 to be dependent upon Claim 268, or alternatively,
ii) moving the limitations of Claim 276 into Claim 275, and cancelling Claim 276.
11. Claim 297 stands 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.
Claim 297 recites 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; of record) 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.
Response to Amendment
While Applicant has amended independent Claim 268 cancelling the limitation, “absence of a systemic immune response”, and instead recite “a reduced level of immune activation or no immune activation”, Applicant did not make said amendment in Claim 297.
12. Claims 268, 275-277, 279, 282-283, and 294 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.
Claim 268 has been amended to recite (b) detecting:
i) a reduced level of immune activation.
The term “reduced level” is a relative term which renders the claim indefinite. The term “reduced level” 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.
Claim 268 has been amended to recite (b) detecting:
i) no immune activation.
The term “immune activation” is a relative term which renders the claim indefinite. The term “immune activation” 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.
As a first matter, and as discussed above, the recitation implies a genus of undisclosed immune responses by which “reduced level” and/or “no immune activation” is/are 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].
As a second matter, the claim fails to recite the reference ‘level of immune activation’ to which “reduced” and/or “no” is to be objectively compared. The subject is unchanging, and thus it is axiomatic that one cannot measure and compare a first ‘level of immune activation’ elicited by the first population of cells relative to a second ‘level of immune activation’ elicited by the first population of cells in the same subject or 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).
13. Claims 268, 275-277, 279, 282-283, 294, and 297 stand 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; of record), 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; of record).
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; of record).
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.
Response to Arguments
Applicant argues that the amendments render the prior rejection moot, more specifically, that it is an amount effect to treat the subject’s disorder.
Applicant’s argument(s) has been fully considered, but is not persuasive.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
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)).
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 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.
14. Claims 268, 275-277, 279, 282-283, 294, and 297 stand 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 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.
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’).
At best, Example 1 [00470-471] discloses administering to a non-human primate 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. No resulting therapeutic effect of the first and/or second cell population is disclosed.
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.
Response to Arguments
Applicant argues that the amendments render the prior rejection moot, more specifically, that it is an amount effect to treat the subject’s disorder.
Applicant’s argument(s) has been fully considered, but is not persuasive. See discussion above.
15. Claims 268, 275-277, 279, 282-283, 294, and 297 stand 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 first cell population genetically modified [structure(s)] to have the functional properties of:
i) decreased expression of one or more MHC-I molecules; and/or
ii) decreased expression of one or more MHC-II molecules; and/or
iii) increased expression of CD47.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
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 claimed genetic modification to decrease expression of one or more MHC-I molecules is/are recited at a high level of generality, whereby the reduced expression may be achieved directly, e.g. by editing the MHC-I locus to a knock-out allele, or reducing expression via siRNA, shRNA, or miRNA, or indirectly, by modulating the expression of a genus of structurally unrecited and undisclosed genes that affect expression of an MHC-I molecule, e.g. blocking surface trafficking of MHC-I or modulating the expression of transcriptional regulators of MHC-I.
The claimed genetic modification to decrease expression of one or more MHC-II molecules is/are recited at a high level of generality, whereby the reduced expression may be achieved directly, e.g. by editing the MHC-II locus to a knock-out allele, or reducing expression via siRNA, shRNA, or miRNA, or indirectly, by modulating the expression of a genus of structurally unrecited and undisclosed genes that affect expression of an MHC-II molecule, e.g. blocking surface trafficking of MHC-II or modulating the expression of transcriptional regulators of MHC-II.
Similarly, the claimed genetic modification to decrease expression of B2M and/or CIITA is/are recited at a high level of generality, whereby the reduced expression may be achieved directly, e.g. by editing the B2M and/or CIITA locus to a knock-out allele, or reducing expression via siRNA, shRNA, or miRNA, or indirectly, by modulating the expression of a genus of structurally unrecited and undisclosed genes that affect expression of B2M and/or CIITA.
Similarly, the claimed genetic modification to increase expression of CD47 is/are recited at a high level of generality, whereby the increased expression may be achieved directly, e.g. by introducing a CD47 transgene, or indirectly, by modulating the expression of a genus of structurally unrecited and undisclosed genes that affect expression of CD47.
The claims fail to recite, and the specification fails to disclose a first modification that necessarily and predictably reduces, directly and/or indirectly, expression of MHC-I by at least 2.5%, but not more than 5%, thereby rendering the cell hypoimmunogenic, as opposed to a second modification that necessarily and predictably reduces, directly and/or indirectly, expression of MHC-I by at least 20%, but not more than 25%, for example.
The claims fail to recite, and the specification fails to disclose a first modification that, while capable of necessarily and predictably reducing, directly and/or indirectly, expression of MHC-II by at least 20%, thereby rendering the cell hypoimmunogenic, is unable to necessarily and predictably reduce, directly and/or indirectly, expression of MHC-II by at least 99%, for example.
The claims fail to recite, and the specification fails to disclose a first modification that necessarily and predictably reduces, directly and/or indirectly, expression of B2M by at least 30%, but not more than 45%, thereby rendering the cell hypoimmunogenic, as opposed to a second modification that necessarily and predictably reduces, directly and/or indirectly, expression of B2M by at least 15%, but not more than 20%, for example.
The claims fail to recite, and the specification fails to disclose a first modification that, while capable of necessarily and predictably reducing, directly and/or indirectly, expression of CIITA by at least 50%, thereby rendering the cell hypoimmunogenic, is unable to necessarily and predictably reduce, directly and/or indirectly, expression of CIITA by at least 75%, for example.
While it is clear that, in one embodiment, the first population of cells have been genetically modified to knockout the endogenous B2M, CIITA genes (B2M-/-, CIITA-/-) (Claims 282-283) and to further comprise a CD47 transgene (Claim 284), thereby increasing expression of CD47 (Example 1, Claim 297), the second population of cells is recited at a high level of generality, and do not even require the genetic modifications of the first population of cells, save that the second population of cells have the functional property of being “hypoimmunogenic”, whereby said limitation suffers from suffers from indefiniteness and lack of adequate written description, as discussed above.
At best, Example 1 [00470-471] discloses 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.
Those of ordinary skill in the art immediately recognize that the claims are far broader in scope than the single species disclosed.
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.
Response to Arguments
Applicant argues that the claims do not require a specific level of reduced MHC I and/or MHC II expression, but rather inactivation or disruption of one or more MHC I and/or MHC II molecules (Claim 268) or modifications to inactivate or disrupt B2M and CIITA (Claim 297).
Applicant’s argument(s) has been fully considered, but is not persuasive. The claimed genetic modification to decrease expression of one or more MHC-I molecules and/or MHC-II molecules is/are recited at a high level of generality, whereby the reduced expression may be achieved directly, e.g. by editing the MHC-II locus to a knock-out allele, or reducing expression via siRNA, shRNA, or miRNA, or indirectly, by modulating the expression of a genus of structurally unrecited and undisclosed genes that affect expression of an MHC-I and/or MHC-II molecule, e.g. blocking surface trafficking of MHC-II or modulating the expression of transcriptional regulators of MHC-II.
Similarly, the claimed genetic modification to decrease expression of B2M and/or CIITA is/are recited at a high level of generality, whereby the reduced expression may be achieved directly, e.g. by editing the B2M and/or CIITA locus to a knock-out allele, or reducing expression via siRNA, shRNA, or miRNA, or indirectly, by modulating the expression of a genus of structurally unrecited and undisclosed genes that affect expression of B2M and/or CIITA.
Similarly, the claimed genetic modification to increase expression of CD47 is/are recited at a high level of generality, whereby the increased expression may be achieved directly, e.g. by introducing a CD47 transgene, or indirectly, by modulating the expression of a genus of structurally unrecited and undisclosed genes that affect expression of CD47.
The claimed genus of genetic modifications is/are recited at a high level of generality that suffers from a lack of adequate written description.
Applicant argues that the specification discloses target genes such as the species disclosed in Table 1 and/or [00283-284].
Applicant’s argument(s) has been fully considered, but is not persuasive. 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). Instant independent claims are broader in scope than the few species disclosed in Table 1 and/or [00283-284].
Absent objective evidence to the contrary, it would be remedial for Applicant to amend the independent claims to positively recite the species disclosed in Table 1 and/or [00283-284], as per Applicant’s argument.
16. Claims 268, 275-277, 279, 282-283, 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.
Applicant has amended independent Claims 268 and 297 to recite “a modification to increase expression of CD47…..relative to a control or wild-type population of cells”.
The phrase “relative to a control or wild-type population of cells” is a relative term which renders the claims indefinite. The term “control” and/or “wild-type population of cells” is/are 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.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The claimed engineered cell is recited at a high level of generality.
The claimed “control” cell is recited at a high level of generality.
The claims fail to recite that which is/are, versus is/are not, a “control” cell, and thus such is considered an arbitrary and subjective determination.
The claimed “wild-type” cell is recited at a high level of generality.
The claims fail to recite that which is/are, versus is/are not, a “wild-type” cell, and thus such is considered an arbitrary and subjective determination.
If there are multiple, structurally and biologically different “control” and/or “wild-type” cells, yet each yields a different amount of CD47 expression levels, then the claim may be indefinite because it is unclear which “control” and/or “wild-type” cell(s) is/are to be referenced in order 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.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
17. Claims 268, 275-277, 279, 282-283, 294, and 297 stand rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
With respect to Step 1, the claims are directed to a process, which is a statutory category of invention (Step 1: YES).
With respect to Step 2A, prong one, the judicial exception, independent Claims 268 and 297 recite the step of “detecting the absence of a systemic immune response” recited at a high level of generality, whereby the step of detecting is an abstract idea or mental thought performed by the artisan, and thus directed to a judicial exception (Step 2A, prong one: YES).
With respect to Step 2A, prong two, the claim does not recite additional elements that integrate the judicial exception into a practical application.
The step of detecting a phenotypic response based upon the observation of the patient, which includes an enormous genus of human and non-human animals, is considered merely extra-solution activity within the biomedical research and medical diagnostic fields of use.
While Claims 268 and 297 recite the step of administering to the patient a therapeutically effective amount of a second population of cells, based on at least the step of detecting the absence of a systemic immune response in the patient after having been administered the first population of cells, here too, the first and second populations of cells are recited at a high level of generality, and the “therapeutically effective amount” is also recited at a high level of generality, and the number of second population of cells to be administered may be any amount, e.g. less than, equal to, or greater than the amount of the first population of cells that were administered.
While it is clear that, in one embodiment, the first population of cells have been genetically modified to knockout the endogenous B2M, CIITA genes (B2M-/-, CIITA-/-) (Claims 282-283) and to further comprise a CD47 transgene (Claim 284), thereby increasing expression of CD47 (Example 1, Claim 297), the second population of cells is recited at a high level of generality, and do not even require the genetic modifications of the first population of cells, save that the second population of cells have the functional property of being “hypoimmunogenic”, whereby said limitation suffers from suffers from indefiniteness and lack of adequate written description.
Further, the phrase “therapeutically effective amount” suffers from indefiniteness and lack of adequate written description, the disease/disorder/condition to be treated is recited at a high level of generality, the claims do not effect a particular treatment of the generically recited patient, and thus these limitations are not considered to integrate the mental step of observation (syn. detecting) and thinking (syn. determining, analysing, concluding) into a practical application (Step 2A, prong two: NO).
With respect to Step 2B, the claims are not considered to recite additional elements that amount to significantly more than the judicial exception itself (Step 2B: NO).
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 administration of the second population of cells is not merely routine or conventional, and thus the claimed methods amount to significantly more than the judicial exception.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, the second population of cells is recited at a high level of generality, and do not even require the genetic modifications of the first population of cells, save that the second population of cells have the functional property of being “hypoimmunogenic”, whereby said limitation suffers from suffers from indefiniteness and lack of adequate written description.
Further, the phrase “therapeutically effective amount” suffers from indefiniteness and lack of adequate written description, the disease/disorder/condition to be treated is recited at a high level of generality, the claims do not effect a particular treatment of the generically recited patient, and thus these limitations are not considered to integrate the mental step of observation (syn. detecting) and thinking (syn. determining, analysing, concluding) into a practical application (Step 2A, prong two: NO).
The claims are not considered to recite additional elements that amount to significantly more than the judicial exception itself (Step 2B: NO).
As a second matter, the prior art cited below contradicts Applicant’s argument that administration of a second population of cells is not merely routine or conventional in art, e.g.:
Feng et al, who taught administering to the patient, based on at least in part the patient’s response to the first population of CAR-T cells, a second population of the CAR-T cells (e.g. pg 4, col. 2, “second cycle”; Figure 2);
Beggs et al, who taught administering to the baboon patient, based on at least in part the baboon patient’s response to the first population of allogeneic baboon MSCs, a second population of allogeneic baboon MSCs (e.g. Abstract; Figure 1); and/or
Wysocynzki et al, who taught that because virtually all of our current knowledge of cell therapy is predicated on the effects of a single cell dose, the idea that the full therapeutic effects of a cell product require repeated doses has far-reaching implications, whereby future studies (both preclinical and clinical) may need to incorporate repeated cell administrations (Abstract). Intuitively, and as a general consideration, expecting one dose of cells to be enough to bring about a therapeutic benefit seems unrealistic (pg 138, col. 1, Introduction). It would appear more sensible to assume that just like pharmacological therapies need to be repeated, so do cell-based therapies. This becomes even more logical when one considers that a major factor limiting the benefits of cell therapy is the poor engraftment of the cells, which disappear rapidly after transplantation, regardless of the type of cell used (pg 138, col. 2). Because of this poor engraftment, it seems self-evident that administering one dose of cells cannot be considered an adequate test of the efficacy of that cell product (pg 139, col. 1).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
18. Claims 268, 275-277, 279, 282-283, 294, and 297 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Feng et al (2017; of record) in view of Beggs et al (2006; of record), Meissner et al (WO 16/183041; of record in IDS), and Wysocynzki et al (July 6, 2018; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 268, Feng et al is considered relevant prior art for having taught a method of treating a disorder in a human patient, the method comprising the step(s) of:
i) administering to the patient a first population of CAR-T cells;
ii) observing an adverse immune response in the patient elicited by the first population of CAR-T cells (e.g. pg 5, col. 2, “chills, fever, fatigue, grade 2 rashes”); and
iii) administering to the patient, based on at least in part the patient’s response to the first population of CAR-T cells, a second population of the CAR-T cells (e.g. pg 4, col. 2, “second cycle”; Figure 2).
Feng et al do not teach ipsis verbis wherein the CAR-T cells are hypoimmunogenic CAR-T cells. However, Feng et al taught wherein the CAR-T cells are autologous to the human patient (e.g. pg 3, col. 2), and thus are understood in the art to be “hypoimmunogenic” relative to non-autologous or allogeneic cells.
Beggs et al 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, based on at least in part the baboon patient’s response to the first population of allogeneic baboon MSCs, 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).
Feng et al taught wherein the first and second cell populations are the same (e.g. Figure 2, CART-EGFR).
Beggs et al taught wherein the first and second cell populations are the same (e.g. Figure 1).
Feng et al do not teach wherein the CAR-T cells are genetically modified to comprise:
i) a knockout B2M mutation;
ii) a knockout CIITA mutation; and/or
iii) a transgene expressing CD47.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 268, 282-283, and 297, Meissner et al is considered relevant prior art for having disclosed a population of hypoimmunogenic cells that have been genetically modified to not express:
i) one or more MHC-I molecules, e.g. gene-edited knockout of the endogenous B2M locus (e.g. pg 2, lines 14-19); and
ii) one or more MHC-II molecules, e.g. gene-edited knockout of the endogenous CIITA locus (e.g. pg 2, lines 14-19), thereby providing a universal donor cell population, wherein the universal donor cells may be T cells, e.g. CAR T cells (e.g. pg 84, line 25).
Meissner et al disclosed wherein the universal donor cells may be further modified to increase the expression of CD47 (e.g. pg 3, lines 9-16).
Meissner et al disclosed that by reducing expression of MHC-I and MHC-II molecules, the universal donor cells are useful for overcoming the immune rejection in cell-based transplantation therapies (e.g. Abstract), and that the expression of a tolerogenic factor such as CD47 inhibits immune rejection (e.g. pg 3, lines 24-25), e.g. prevents engulfment of cells from macrophages (e.g. pg 16, line 11, “high levels of CD47, the human ‘don’t eat me’ signal).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, immunology, genetics, and cell transplantation therapies. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Wysocynzki et al is considered relevant prior art for having taught that because virtually all of our current knowledge of cell therapy is predicated on the effects of a single cell dose, the idea that the full therapeutic effects of a cell product require repeated doses has far-reaching implications. For example, inadequate dosing (single-dose protocols) may be responsible, at least in part, for the borderline or disappointing results obtained to date in clinical trials; furthermore, future studies (both preclinical and clinical) may need to incorporate repeated cell administrations (Abstract).
Intuitively, and as a general consideration, expecting one dose of cells to be enough to bring about a therapeutic benefit seems unrealistic (pg 138, col. 1, Introduction). It would appear more sensible to assume that just like pharmacological therapies need to be repeated, so do cell-based therapies. This becomes even more logical when one considers that a major factor limiting the benefits of cell therapy is the poor engraftment of the cells, which disappear rapidly after transplantation, regardless of the type of cell used (pg 138, col. 2). Because of this poor engraftment, it seems self-evident that administering one dose of cells cannot be considered an adequate test of the efficacy of that cell product (pg 139, col. 1).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to modify the CAR-T cells of Feng et al to further comprise:
i) a knockout B2M mutation; and/or
ii) a knockout CIITA mutation; and/or
iii) a transgene expressing CD47,
with a reasonable expectation of success and motivation because Meissner et al disclosed that CAR-T cells may comprises said (i), (ii), and (iii) genetic modifications, and that by reducing expression of MHC-I and MHC-II molecules, e.g. via knockout of the endogenous B2M and CIITA genes, respectively, and expressing transgenic CD47, the universal donor cells are useful for overcoming and/or inhibiting the immune rejection in cell-based transplantation therapies.
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to arrive at a CAR-T method of treating cancer in a patient, wherein the CAR-T cells are genetically modified to further comprise:
i) a knockout B2M mutation; and/or
ii) a knockout CIITA mutation; and/or
iii) a transgene expressing CD47,
to comprise the step of detecting the presence and/or absence of a systemic immune response in the patient elicited by the CAR-T cells prior to administering at least a second dose of CAR-T cells based on the presence and/or absence of at least one systemic immune response, with a reasonable expectation of success because those of ordinary skill in the art previously recognized the scientific, clinical, and technical concepts that:
a) CAR-T cell therapy is commonly recognized in the art to elicit one or more adverse immune responses in the patient (e.g. Feng et al, pg 6, col. 1, “according to the common terminology criteria for adverse events 4.0 (CTCAE 4.0)”);
b) intuitively, and as a general consideration, expecting one dose of cells to be enough to bring about a therapeutic benefit seems unrealistic, it is more sensible and logical to assume that just like pharmacological therapies need to be repeated, so do cell-based therapies, and thus self-evident that administering one dose of cells cannot be considered an adequate test of the efficacy of that cell product (Wysocynzki et al); and
c) the step of detecting the presence and/or absence of one or more systemic immune responses in a patient elicited from the first population of hypoimmunogenic cells, prior to administering a second population of hypoimmunogenic cells was previously successfully demonstrated, so as to safely allow their transplantation, including, but not limited to, without the use of pharmacologic immunosuppression (Beggs et al).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 275-276, Feng et al taught wherein the second population of CAR-T cells were administered to the human patient at least 2 months or at least 6 months after the first population of CAR-T cells were administered (e.g. pg 4, col. 2; Figure 2).
Beggs et al taught wherein there is a recovery period between the administration of the first cell population and the administration of the second cell population, e.g. at least 6 weeks between doses (e.g. Figure 1).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
With respect to Claims 277 and 279, Feng et al do not teach administering an immunosuppressive agent at least 2 days after the administration of the first population of cells.
Beggs et al do not teach administering an immunosuppressive agent at least 2 days after the administration of the first population of cells (e.g. Abstract, “without the use of pharmacologic immunosuppression”; Figure 1).
With respect to Claim 294, Feng et al taught wherein the disorder is cancer, more specifically, gastrointestinal cancer (e.g. Title, Background).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that Feng et al do not teach the genetic modifications of the independent claims.
Applicant’s argument(s) has been fully considered, but is not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Meissner et al is considered relevant prior art for having disclosed a population of hypoimmunogenic cells that have been genetically modified to not express:
i) one or more MHC-I molecules, e.g. gene-edited knockout of the endogenous B2M locus (e.g. pg 2, lines 14-19); and
ii) one or more MHC-II molecules, e.g. gene-edited knockout of the endogenous CIITA locus (e.g. pg 2, lines 14-19), thereby providing a universal donor cell population, wherein the universal donor cells may be T cells, e.g. CAR T cells (e.g. pg 84, line 25).
Meissner et al disclosed wherein the universal donor cells may be further modified to increase the expression of CD47 (e.g. pg 3, lines 9-16).
Applicant argues that the ordinary artisan would not have been motivated to combine the teachings of Feng et al (CAR-T therapy) with Beggs et al (baboon MSCs)
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner must determine what is "analogous prior art" for the purpose of analyzing the obviousness of the subject matter at issue. **>"Under the correct analysis, any need or problem known in the field of endeavor at the time of the invention and addressed by the patent [or application at issue] can provide a reason for combining the elements in the manner claimed. " KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). Thus a reference in a field different from that of applicant's endeavor may be reasonably pertinent if it is one which, because of the matter with which it deals, logically would have commended itself to an inventor's attention in considering his or her invention as a whole.<
Both Feng et al and Beggs et al successfully demonstrated that those of ordinary skill in the art previously recognized the scientific, clinical, and technical concepts of:
i) administering to the subject/patient a first population of cells (Feng et al, CAR-T cells; Beggs et al, baboon MSCs);
ii) observing and/or detecting an immune response in the subject/patient elicited by the first population of cell; and
iii) administering to the subject/patient, based on at least in part the subject’s/patient’s response to the first population of cells, a second population of the cells.
Applicant argues that Meissner et al do not make up for the deficiencies of Feng et al and Beggs et al.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Both Feng et al and Beggs et al successfully demonstrated that those of ordinary skill in the art previously recognized the scientific, clinical, and technical concepts of:
i) administering to the subject/patient a first population of cells (Feng et al, CAR-T cells; Beggs et al, baboon MSCs);
ii) observing and/or detecting an immune response in the subject/patient elicited by the first population of cell; and
iii) administering to the subject/patient, based on at least in part the subject’s/patient’s response to the first population of cells, a second population of the cells.
Meissner et al is considered relevant prior art for having disclosed a population of hypoimmunogenic cells that have been genetically modified to not express:
i) one or more MHC-I molecules, e.g. gene-edited knockout of the endogenous B2M locus (e.g. pg 2, lines 14-19); and
ii) one or more MHC-II molecules, e.g. gene-edited knockout of the endogenous CIITA locus (e.g. pg 2, lines 14-19), thereby providing a universal donor cell population, wherein the universal donor cells may be T cells, e.g. CAR T cells (e.g. pg 84, line 25).
Meissner et al disclosed wherein the universal donor cells may be further modified to increase the expression of CD47 (e.g. pg 3, lines 9-16).
Applicant argues that Wysocynski et al do make up for the deficiencies of Feng et al, Beggs et al, and Meissner et al.
Applicant’s argument(s) has been fully considered, but is not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Both Feng et al and Beggs et al successfully demonstrated that those of ordinary skill in the art previously recognized the scientific, clinical, and technical concepts of:
i) administering to the subject/patient a first population of cells (Feng et al, CAR-T cells; Beggs et al, baboon MSCs);
ii) observing and/or detecting an immune response in the subject/patient elicited by the first population of cell; and
iii) administering to the subject/patient, based on at least in part the subject’s/patient’s response to the first population of cells, a second population of the cells.
Meissner et al is considered relevant prior art for having disclosed a population of hypoimmunogenic cells that have been genetically modified to not express:
i) one or more MHC-I molecules, e.g. gene-edited knockout of the endogenous B2M locus (e.g. pg 2, lines 14-19); and
ii) one or more MHC-II molecules, e.g. gene-edited knockout of the endogenous CIITA locus (e.g. pg 2, lines 14-19), thereby providing a universal donor cell population, wherein the universal donor cells may be T cells, e.g. CAR T cells (e.g. pg 84, line 25).
Meissner et al disclosed wherein the universal donor cells may be further modified to increase the expression of CD47 (e.g. pg 3, lines 9-16).
Wysocynzki et al is considered relevant prior art for having taught that because virtually all of our current knowledge of cell therapy is predicated on the effects of a single cell dose, the idea that the full therapeutic effects of a cell product require repeated doses has far-reaching implications. For example, inadequate dosing (single-dose protocols) may be responsible, at least in part, for the borderline or disappointing results obtained to date in clinical trials; furthermore, future studies (both preclinical and clinical) may need to incorporate repeated cell administrations (Abstract).
Intuitively, and as a general consideration, expecting one dose of cells to be enough to bring about a therapeutic benefit seems unrealistic (pg 138, col. 1, Introduction). It would appear more sensible to assume that just like pharmacological therapies need to be repeated, so do cell-based therapies. This becomes even more logical when one considers that a major factor limiting the benefits of cell therapy is the poor engraftment of the cells, which disappear rapidly after transplantation, regardless of the type of cell used (pg 138, col. 2). Because of this poor engraftment, it seems self-evident that administering one dose of cells cannot be considered an adequate test of the efficacy of that cell product (pg 139, col. 1).
19. Claim(s) 294 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Feng et al (2017; of record) in view of Beggs et al (2006; of record), Meissner et al (WO 16/183041; of record in IDS), and Wysocynzki et al (July 6, 2018; of record), as applied to Claims 268, 275-277, 279, 282-283, 294, and 297 above, and in further view of Kansal et al (available online March 6, 2019; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Neither Feng et al nor Meissner et al teach/disclose wherein the disease/disorder/condition to be treated is lupus.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 294, Kansal et al is considered relevant prior art for having taught a method of treating lupus in mouse patients, the method comprising the step(s) of administering to said mouse patients autologous CAR-T cells (e.g. pg 2, col. 1, Figure 1; pg 2, col. 2, Methods).
As discussed above, those of ordinary skill in the art understood autologous T cells to be “hypoimmunogenic” relative to non-autologous or allogeneic cells.
Kansal et al taught wherein the autologous CAR-T cells led to a lasting remission of lupus, sustained B cell depletion preventing auto-antibody production, alleviated manifestations of lupus pathogenesis, and lengthened life spans well-beyond non-CAR-T mouse patients (e.g. Abstract, Introduction, Figure 4A-B).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute cancer, as taught by Feng et al and Meissner et al, with lupus, as taught by Kansal et al, in a CAR-T immunotherapy method with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute cancer with lupus in a CAR-T immunotherapy method because Kansal et al taught wherein the autologous CAR-T cells led to a lasting remission of lupus, sustained B cell depletion preventing auto-antibody production, alleviated manifestations of lupus pathogenesis, and lengthened life spans well-beyond non-CAR-T mouse patients (e.g. Abstract, Introduction, Figure 4A-B).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that Kansal et al do make up for the deficiencies of Feng et al, Beggs et al, and Meissner et al, and Wysocynski et al.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner’s response to Applicant's argument(s) regarding Feng et al, Beggs et al, and Meissner et al, and Wysocynski et al are discussed above and incorporated herein. Applicant does not contest the teachings of Kansal et al as applied to the obviousness to substitute cancer, as taught by Feng et al and Meissner et al, with lupus, as taught by Kansal et al, in a CAR-T immunotherapy method with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute cancer with lupus in a CAR-T immunotherapy method because Kansal et al taught wherein the autologous CAR-T cells led to a lasting remission of lupus, sustained B cell depletion preventing auto-antibody production, alleviated manifestations of lupus pathogenesis, and lengthened life spans well-beyond non-CAR-T mouse patients (e.g. Abstract, Introduction, Figure 4A-B).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Citation of Relevant Prior Art
20. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Lee et al (Highly Efficient, ZFN-Driven Knockout of Surface Expression of the T-Cell Receptor and HLA Class I Proteins in Human T-Cells for Enhancing Allogeneic Adoptive Cell Therapies, Molecular Therapy 24 (Suppl 1): S254, Abstract 641, May 2016; of record) is considered relevant prior art for having taught a population of hypoimmunogenic T cells whose genomes have been edited to knockout the B2M gene, thereby reducing expression of MHC HLA class I proteins.
Conclusion
21. 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
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