DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
Priority
The instant application, filed 07/14/2022, is a 371 filing of PCT/US2021/013521, filed 01/14/2021, which claims domestic benefit to US provisional applications 63/016,256, filed 04/27/2020, 63/015,476, filed 04/24/2020, and 62/961,200, filed 01/14/2020.
Status of Claims/Application
Applicant’s preliminary amendment of 10/03/2025 is acknowledged. Claims 5, 25, 48, and 53 are amended and claims 23-24 are cancelled. Claims 1-22 and 25-55 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/14/2022, 06/04/2025, and 12/22/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
The specification filed 07/14/2022 comprises the following sequence without an accompanying SEQ ID NO on page 150, lines 5-6: Asp-Val/Ile-Glu-X-Asn-Pro-Gly-Pro.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification Objection
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The following embedded hyperlinks were identified in the specification filed 07/14/2022. Prefix and non-top-level domain browser-executable code is bolded for clarity.
Page 16, line 22: https://doi.org/10.1016/j.biopha.2019.109625
Page 162, line 11: http://www.IRESite.org
Claim Objections
Claim 1 is objected to because of the following informalities:
the claim is missing the conjunction “and” between steps (c) and (d).
lines 8-9 of the claim recites “the ECD of a an orthogonal hCD122”. Removal of the extraneous “a” is suggested; and
line 16 recites “a orthogonal ligand”. Correction of the “a” to “an” is suggested.
Claim 9 is objected to because of the following informality: the claim recites “the vector comprises the two nucleic acid sequences are separated by”. The wording of the recitation is grammatically incorrect. It is suggested that the recitation be modified, for instance, by removing the “are” between “sequences” and “separated” or by adding “which” before the “are”. Appropriate correction is required.
Claims 15-16, 26, 40-41, and 47 are objected to because of the following informality: the claims are missing periods at the end. Appropriate correction is required.
Claims 19-21 are objected to because of the following informality: the claims recite “the disease, disorder of condition”. Correction to “the disease, disorder, or condition”, as is recited in instant claim 1, is suggested.
Claim 21 is objected to because of the following informality; the claim recites “a inflammatory disease”. Correction of “a” to “an” is suggested.
Claim 25 is objected to because of the following informality: part (B)(i) of the claim further limits the tumor antigens that the CAR specifically binds. The claim recites GD3, CD123, CD22, mesothelin, and FAP twice. Correction to remove the redundant limitations is suggested.
Claim 31 is objected to because of the following informality: the claim recites the sequence “YLRQ” twice. Removal of the redundant limitation or clarification is suggested.
Claim 48 is objected to because of the following informalities: line 2 of the claim recites “(a)”. The recitation appears to be extraneous as the claim does not recite any other lettered lists (such as “(b)”). Correction to remove the extraneous letter numbering is suggested.
Additionally, the definition of AA27 recites “AA27 IS G (wildtype), K, S, or deleted”. The “IS” should be lowercase. Appropriate correction is suggested.
Additionally, the claim recites “wild type” and “wildtype” in the definitions for the amino acids. The correct syntax in the context recited is “wild-type” correction for consistency and accuracy is suggested.
Claim 52 is objected to because of the following informality: the claim recites a formula for the PEGylated hoIL2 ortholog as “[PEG]-[linker]-[desAla1-hIL2[E15S-H16Q-L19V-D20L-Q22K-M23A]”. The last segment of the formula is missing a closing bracket.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-11, 12, 14, 16-18, 25-53, and 55 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 2 depends on claim 1 and limits the population of cells to comprising one or more species of human immune cells from the recited list. The list includes CAR-T cells, which is not a species of human immune cell, but rather a modified cell, rendering the metes and bounds of the claim indefinite.
Claim 9 recites the limitation that the two nucleic acid sequences are separated by “an IRES element of T2A coding sequence”. IRES and T2A are two distinct sequences and T2A does not comprise an IRES element. As such, it is unclear how the IRES can be an element of the T2A coding sequence as recited, rendering the metes and bounds of the claim indefinite.
Appropriate correction is required.
Claims 10 and 11 are rejected by virtue of their dependency on claim 9 as they do not resolve the ambiguity discussed above.
In the instant office action, the limitation is interpreted as being an IRES element or a T2A coding sequence.
Claim 12 depends on claim 1 and recites “the orthogonal ligand employed ex vivo in step (b)” and “the orthogonal ligand used in vivo in step (c)”. There is insufficient antecedent basis for these limitations in the claim rendering the metes and bounds of the claim indefinite. Claim 1 part (b) does not recite an orthogonal ligand employed ex vivo and part (c) does not recite an orthogonal ligand used in vivo.
Appropriate correction is required.
In the instant office action, the limitations are interpreted as referencing steps (c) and (d).
Claim 14 depends on claim 1 and recites “the initial dose administered in step (d)”. There is insufficient antecedent basis for this limitation in the claim. Claim 1, step (d) recites administering a therapeutically effective quantity of the cells from step (c) to the mammalian subject; however, the claim does not recite an “initial dose” that could be being referenced nor does the claim recite multiple dosages such that an initial dose is included in the administration step, rendering the metes and bounds of claim 14 indefinite.
Claims 16-17 recite the limitations “no substantial sign of remaining tumor”. There is insufficient basis for the tumor recited in the claims. Claim 1 is drawn to the treatment or prevention of a disease, disorder, or condition and does not recite a tumor or cancer that could be being used as a reference point in order to determine that there is no substantial sign of the tumor remaining.
Claim 18 is rejected by virtue of its dependency on claim 17 as it does not resolve the ambiguity discussed above.
Claim 18 depends on claim 1 an recites “the initial course of immune cell therapy” There is insufficient antecedent basis for this limitation in the claim. Claim 1, step (d) recites administering a therapeutically effective quantity of the cells form step (c) to the mammalian subject; however, the claim does not recite an initial course that could be being referenced rendering the metes and bounds of the claim indefinite.
Claim 25 part (B)(i) recites “ROR CD44”. There is no art recognized antigen ROR CD44 rendering the metes and bounds of the claim indefinite. In so far as these could be interpreted as two separate antigens with a missing comma between them, there is also no art recognized antigen “ROR”. The closest antigen in the art is ROR1, which, it is noted, is already recited in the claim.
Appropriate correction is required.
Claims 26-53 are rejected by virtue of their dependency on a rejected claim as they do not resolve the ambiguity discussed above.
Claim 27 recites “the intracellular domain of human IL4 receptor Type II receptor subunit a (hIL4Ra) (SEQ ID NO: 9), the intracellular domain of human IL-7 receptor subunit a (hIL7Ra) (SEQ ID NO: 11), the intracellular domain of human IL9 receptor (hIL9R) (SEQ ID NO: 13), and the intracellular domain of human IL21 receptor (hIL21R) (SEQ ID NO: 15).” The inclusion of the SEQ ID NOs in parentheticals renders the scope of the claim indefinite as the sequences recited are a narrower embodiment of the preceding limitations. For instance, while human IL-7 receptor subunit a has a specific sequence, the sequence recited in the parentheticals is only a portion of this sequence. As such, it is unclear if the claimed intracellular domain is limited to the specific sequence recited within the parentheticals or if a longer or shorter portion of the hIL7R sequence would meet the instant claim limitation. As the scope of the claim is unclear, the claim is indefinite.
Appropriate correction is required.
Claim 31 recites the following: “YLRQ (SEQ ID NO: 11); YLKQ (SEQ ID NO: 12); YRHQ (SEQ ID NO: 13); YLRQ (SEQ ID NO: 14); YFKQ (SEQ ID NO: 15)”. In each of these instances, the SEQ ID NOs (SEQ ID NOs: 11-15) are not the same as the preceding sequences recited. As the SEQ ID NOs recited are not the same as the recited sequences, the metes and bounds of the claim are indefinite as it is unclear what sequence is being claimed.
Appropriate correction is required.
Regarding claim 42, the use of “e.g." renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The claim recites “helper T cells, e.g. TH1…”; “regulatory T cells, e.g., TR1…”; and “memory T cells, e.g., central memory T cells…” In each instance, the limitations following “e.g.” are narrower embodiments of the preceding limitations. 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 42 recites broad recitations, and the claim also recites narrower limitations following “e.g.” which are 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.
Claim 48, the instant claim recites an orthogonal IL-2 (hoIL2) and recites that the hoIL2 polypeptide has a sequence at least 95% identical to SEQ ID NO: 50. As recited, the claim encompasses the sequence of human IL-2 (when all of the amino acid variables are wild type). As such, it is unclear if the wild type human IL-2 meets the limitation of an orthogonal IL-2 or if a modification in human IL-2 is required in order to meet the limitation of the IL-2 being orthogonal, rendering the metes and bounds of the claim indefinite.
Additionally, line 6 of the claim recites the variable “(AA9)i”. Neither “(AA9)i” together nor “i” alone are defined in the claim, which provides a definition only for AA9, rendering the metes and bounds of the claim indefinite.
Regarding claim 55, part (a) recites “an orthogonal GPC3 receptor polypeptide” and recites that the polypeptide is SEQ ID NO: 29. Instant SEQ ID NO: 29; however, is the sequence of an orthogonal CD122 receptor, not an orthogonal GPC3 receptor polypeptide as claimed. It is unclear if an orthogonal GPC3 receptor polypeptide is claimed or the sequence, which is that of an orthogonal CD122. The last paragraph of the claim also references “the orthogonal CD122 receptor polypeptide”, which could be interpreted as having antecedence to instant SEQ ID NO: 29, but SEQ ID NO: 29 is identified in the claim as an orthogonal GPC3 receptor polypeptide.
In the instant office action, the claim is interpreted as being drawn to the orthogonal CD122 polypeptide of SEQ ID NO: 29.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
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.
Claim 31 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 31 depends on claim 30 and recites that the polypeptide of the formula YX1X2Q is a polypeptide selected from the recited group, which includes a polypeptide of YDKPH (SEQ ID NO: 18). The polypeptide of YDKPH; however, is not a species of the formula YX1X2Q that is recited in claim 30. As the claim encompasses polypeptides outside of the formula recited in claim 30, the claim is broader than claim 30 and does not include all of the limitation of the claim upon which it depends.
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.
Claim Rejections - 35 USC § 112(a)
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.
Scope of Enablement
Claims 1-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating or suppressing, inhibiting, or reducing the risk of developing a disease, disorder or condition, does not reasonably provide enablement for preventing a disease, disorder, or condition. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
The instant claims are drawn to a method of treating or preventing a disease, disorder, or condition in a mammalian subject comprising the recited steps in which immune cells are isolated from the subject; engineered with a nucleic acid sequence encoding a transmembrane receptor with an ECD of an orthogonal hCD122; contacted ex vivo with an orthogonal ligand sufficient to induce proliferation; and administered to the mammalian subject in combination with the administration of a therapeutically effective dose of an orthogonal ligand.
The breadth of the claims
The claims are broad in that they encompass prevention of any disease, disorder, or condition. The specification defines “prevent”, “preventing”, “prevention” and the like as referring to a course of action initiated with respect to a subject prior to the onset of a disease, disorder or condition or symptom thereof as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject’s risk of developing a disease, disorder or the like or delaying the onset thereof.
As such, the term “preventing” encompasses a course of action taken to prevent the development of a disease, disorder or condition in a subject prior to onset.
Wojtczak, A. (2002) Glossary of Medical Education Terms Medical Teacher 24(4): 357; 1-25 (“IIME”) defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (page 16, “Prevention”). IIME states that “primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe.” IIME states that “secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health”. IIME further states that tertiary prevention consists of the measures available to reduce or eliminate long-term impairments and disabilities, minimize suffering caused by existing departures from good health”.
Thus, in its broadest reasonable interpretation, the prevention of a disease, disorder, or condition suggests that that the onset of the condition never occurs and the patient’s health is protected and preserved.
The amount or direction provided by the inventor / the existence of working examples
The examples of the instant disclosure demonstrate the generation of orthogonal IL-2 expression vectors, the transient transfection of the vectors into HEK293 cells, and the analysis of protein expression (examples 1-5). The examples further studied the activity of the orthogonal IL-2 generated in cell lines expressing hoCD122 (example 6). The examples studied the efficacy of orthogonal CAR-T cells in combination with a cognate orthogonal ligand in a mouse leukemia model using a CD19 CAR in addition to the hoCD122 receptor (page 186, example 7). In the study, mice were implanted with tumor cells on day 0 which were allowed to grow for 5 days prior to administration of the modified cells. The example demonstrates that the presence of the hoCD122 receptor provided additional anti-tumor function compared to CD19 alone. Similar studies are provided in Raji Lymphoma solid tumor models (page 192, Example 8) and in RAJI-luc lymphoma rechallenge models (page 196, Example 9) where mice that were cured in the previous study were rechallenged with the tumor cells. The examples also demonstrate treatment of the lymphoma after relapse (page 196, example 10).
While the examples demonstrate treatment of tumors, as well as inhibition of tumor formation during rechallenge, these studies are only provided when the hoCD122 receptor is in an immune cell with a CAR. Additionally, the studies do not demonstrate the prevention of the onset of any disease, disorder, or condition.
The disclosure also does not identify a method that could be used by one of ordinary skill in the art to determine that a subject would have predictably experienced the onset of a disease, disorder, or condition in order to establish that the onset was effectively prevented using the claimed method.
The state of the prior art / the level of predictability in the art
The state of the prior art also demonstrates unpredictability in predicting the onset of disease, disorders, and conditions. For instance, the art teaches the following regarding cancer, infectious disease, and inflammatory/autoimmune diseases.
Lewandowska, A.M., et al (2017) Environmental risk factors for cancer – review paper Ann. Agric. Environ. Med. 26(1); 1-7 teaches that the cancerous process is a result of disturbed cell function. This is due to the accumulation of many genetic and epigenetic changes within the cell, expressed in the accumulation of chromosomal or molecular aberrations, which leads to genetic instability. It is difficult to assess the validity of individual etiological factors, but it can be concluded that interaction of various risk factors has the largest contribution for the development of cancer. Environmental, exogenous and endogenous factors, as well as individual factors, including genetic predisposition, contribute to the development of cancer (page 1, right column, paragraph 1). Lewandowska discusses numerous factors that contribute to the development of cancer including physical factors such as exposure to electromagnetic fields, ionizing radiation, and ultraviolet radiation (pages 2-3); chemical factors including tobacco smoking, alcohol, and other chemicals (pages 3-4); and biological factors including diet, physical activity, mutagenic and carcinogenic compounds in food, nitrosoamines, and infections (pages 4-5). Lewandowska teaches that, additionally, some epidemiological research suggests that the influence of environmental factors will further affect the cell’s genetic material. This is connected with the spreading of carcinogens in various geographical zones. While some are well known and can be modified, there are certain factors that cannot be fully controlled, such as industrialization (page 6, left column, paragraph 2).
The teachings of Lewandowska demonstrate that, while it was known that cancer is caused by disturbed cell function, numerous factors were known that could lead to such disfunction and cell disfunction is likely caused by the interaction of various risk factors. Lewandowska also teaches factors such as genetic predisposition and environmental factors that could contribute to the formation of cancer but are beyond the control of an individual subject. These teachings demonstrate that there was no specific known cause of cancer and, therefore, suggest that there would be no method to predictably determine that cancer was prevented using the claimed method.
McArthur, D.B. (2019) Emerging infectious diseases Nurs. Clin. N. Am. 54; 297-311 discusses emerging infectious diseases and teaches that new infections could be the result of changes or evolution of existing organisms, known infections spreading to new geographic areas or populations, previously unrecognized infections appearing in areas undergoing ecologic transformation, or old infections reemerging because of antimicrobial resistance in known agents or breakdowns in public health measures. Emerging infections account for at least 15% of all human pathogens and are a major concern and can be zoonotic, synoptic, foodborne, vector-borne, or airborne. Regardless, for an infectious disease to become established, the infectious agent must be introduced into a vulnerable population and have the ability to spread (abstract). McArthur teaches that infectious diseases are inevitable and unpredictable (page 308, paragraph 3).
The teachings of McArthur demonstrate that new infectious diseases are constantly emerging and that the diseases are unpredictable. These teachings demonstrate that there was no known method to predict infectious disease suggesting that identifying subjects who would develop an infectious disease was also unpredictable. As such, there was no known method that could be used to predictably identify subjects for whom infectious disease was prevented using the claimed methods.
Rosenblum, M.D., et al (2015) Mechanisms of human autoimmunity J Clin Invest 125(6); 2228-2233 teaches that autoimmune diseases are a significant clinical problem. Current therapies have shown great promise in many of these diseases. However, most of the current therapeutic agents target the terminal phase of inflammation and do not address the fundamental problems that are responsible for the initiation and progression of the autoimmune process. Tackling these diseases at their source will require understanding of how the abnormal immune reactions arise, how they are sustained and the intrinsic mechanisms used to suppress these responses in healthy individuals (page 2228, left column, paragraph 1). Rosenblum teaches that because most patients with autoimmune disease develop symptoms well after the abnormal immune reaction begins, it is often difficult to pinpoint the factors responsible for the initiation of disease. Although animal models are informative, there are in fact few models of spontaneous autoimmunity that reliably mimic the human disorders (page 2228, paragraph bridging columns). Autoimmune diseases, like many other complex disorders, are believed to arise from a combination of genetic and environmental factors (page 2228, right column, paragraph 1). Rosenblum teaches factors that are thought to cause autoimmune related diseases including genetic predisposition, such as HLA alleles, cytokine and cytokine receptor genetic polymorphisms, and polymorphisms of multiple genes involved in human immune functioning; environmental triggers, such as infection, microbiome, and traumatic triggers; and defective regulation of the immune system (page 2230, Figure 2). Rosenblum teaches that understanding and successfully treating human autoimmune disease continues to be a significant challenge but incredible progress has been made. Although we have yet to be able to successfully prevent the match from being lit, we are making serious headway in dampening the flames and, in some cases, extinguish the fire (page 2232, paragraph bridging columns).
The teachings of Rosenblum demonstrate that the onset of autoimmune disease/inflammatory diseases was not predictable and that there were numerous potential factors that had been studied as potential causes of the diseases. The references demonstrate that there were no established methods to determine that a subject would have predictably developed an autoimmune or inflammatory disease and, therefore, there is no method that could be used to determine that the diseases were prevented with the claimed method.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed in detail above, there is no disclosed or art recognized method through which an ordinarily skilled artisan would be able to determine that a subject would have predictably developed a disease, disorder, or condition, including cancer, chronic infection, or inflammatory disease, in order to apply the claimed method as a preventative measure. Furthermore, there is no method identified that one of ordinary skill in the art could use to predictably identify a subject who would have developed a disease, disorder, or condition in order to establish that said disease, disorder, or condition was prevented using the claimed method. Therefore, in order to implement the invention as claimed, one of ordinary skill in the art would have to participate in undue experimentation to find a method that could be used to determine that a disease, disorder, or condition was prevented, with the possibility that no such method could be found.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
Written Description
Claim 48 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.
Instant claim 48 is drawn to a method of treating a mammalian subject suffering from a neoplastic disease, the method comprising administering a therapeutically effective amount of an orthogonal mammalian CAR T cell of claim 25 in combination with a therapeutically effective amount of an hIL2 ortholog. The claim further limits the hoIL2 polypeptide to having at least 95% identity to the polypeptide of the formula presented in the claim in which 40/133 positions can also be varied either by deletion or by alternative amino acids. As such, the claims are drawn to a genus of hoIL2 polypeptide structures, which are limited by the function of being able to treat a mammalian subject suffering from a neoplastic disease when administered with the orthogonal CAR T cell of claim 25.
Claim 25, on which claim 48 depends, recites an orthogonal mammalian CAR T cell comprising a first nucleic acid that encodes a signal peptide and an orthogonal receptor, the orthogonal receptor comprising a signal peptide, an extracellular domain, a transmembrane, and an intracellular signaling domain. The claim further limits the extracellular signaling domain to comprising a peptide as recited in claim 25, part (i).
As discussed above, claim 48 encompass a genus of hoIL2 polypeptides with varying structure all of which are claimed as having the recited function of treating a neoplastic disease, a function which requires that the hoIL2 polypeptide bind to the orthogonal receptor that is in claim 25 resulting in signaling from the receptor.
The instant disclosure; however, does not provide a representative number of species of the claimed genus performing the claimed function, nor does the disclosure identify a structure-function correlation that would allow for the predictable identification of which species of the genus would be capable of performing the claimed function.
The examples of the instant disclosure studied the introduction of mutations or back mutations into wild type human IL2 as reported in example 3 on page 181. In the example, mutations are made in positions 15, 16, 19, 20, 22, and/or 23 of either the IL2 peptide or an ortho peptide comprising mutations in positions 35, 36, 39, 40, 42 and 43 as outlined in example 2, page 181. The example further studied the expression level of the IL2 orthologs in Example 5, Table 8. The IL2 orthologs were also tested in cell lines expressing hoCD122 (Example 6, page 185).
The examples demonstrate the IL2 orthologs identified as SQVLKA, SQ----, SQVL--, -QVLKA, S-VLKA, SQ-LKA, SQV-KA, SQVL-A, SQVLK-, E15S, H16Q, L19V, D20L, Q22K, and M23A and their binding to the hoCD122 receptor. The examples further demonstrate the use of a pegylated hoIL2 of STK-009, which comprised [desAla1-E15S-H16Q-L19V-D20L-Q22A-C125A] with numbering according to SEQ ID NO: 23.
These IL2 orthologs represent the species of the claimed genus that applicant was in possession of at the time of the effective filing date of the claimed invention.
The disclosure further identifies that hIL2 orthologs can contain one or more mutations in positions of the hIL2 sequence that either contact hCD122 or alter the orientation of other positions contacting CD122, resulting in an IL2 ortholog having an increased affinity of CD122. The specification further teaches that IL2 orthologs contain one or more mutations in the positions of the IL2 sequence that either contact CD25 or alter the orientation of the IL2 contacting CD25 resulting in a decreased affinity for CD25. The disclosure also identifies mutations in positions of IL2 that contact CD132 or alter binding to CD132 (page 40, [0376]- page 41, [0404]). The specification also provides known residues that are involved in each of these binding interfaces. The specification further details modifications that can be made to delete the N-terminal Met-Ala1, conservative amino acid substitutions, removal of glycosylation sites, oxygen stabilization, and N-terminal deletions.
While the disclosure identifies these positions as ones that can be modified to reduce natural IL2 binding, and potentially improve the IL2 polypeptide, the disclosure does not demonstrate that IL2 peptides across the entire scope of the orthogonal IL2 peptide claimed in the instant claim would be capable of binding to the orthogonal CD122 receptor recited in instant claim 25 leading to the treatment of a neoplastic disorder. For instance, in the broadest reasonable interpretation of the claim, all of the variable amino acids could be deleted and an additional 5% modification (95% identity) could be made anywhere in the remaining structure. The disclosure does not provide any expectation or demonstration that the deletion of all 40/133 amino acids would result in an orthogonal IL-2 that is capable of treating a mammalian subject suffering from a neoplastic disease when administered with the orthogonal mammalian CAR T cell of claim 25, as claimed.
The disclosure does not provide a representative number of species of the claimed hoIL2 polypeptide performing the claimed function nor does the disclosure provide a structure-function correlation that would allow for the predictable identification of which species in the full scope of the claimed genus would be capable of performing the claimed functions.
The prior art also does not provide a representative number of the claimed species performing the claimed functions nor does the art provide a structure-function correlation that could be used to predictably identify which species of the claimed hoIL-2 would be capable of performing the claimed functions.
For instance, Tang, A. and F. Harding (2019) The challenges and molecular approaches surrounding interleukin-2-based therapeutics in cancer Cytokine: X 1 (100001); 1-9 teaches that IL-2 has had a long history as a promising cancer therapeutic, being capable of eliciting complete and durable remissions in patients with metastatic renal cell carcinoma and metastatic melanoma. Despite high toxicity and efficacy limited to only certain subpopulations and cancer types, the prospective use of novel, engineered IL2 formats in combination with the presently expanding repertoire of immune-oncological targets remains very encouraging. This is possible due to the significant research efforts in the field of IL2 that have yielded critical structural and biological insights that have made IL2 more effective and more broadly applicable. Tang provides a review of molecular approaches used to further improve IL2 cancer therapy (abstract).
Tang teaches that IL2 engineering strategies have included the production of IL-2 muteins, in which IL2 function has been modified by introducing targeted mutations, where even a few specific changes can have profound effects on toxicity. Mutations introduced in IL2 are typically target at sites known to bind CD25, CD122, or CD132 (pages 2-3, 3.1). Tang further discusses mutations affecting CD25, CD122, and CD132 binding. With regards to CD25 binding, Tang teaches that mutations that disrupt CD25 binding are typically employed to preferentially direct IL2 stimulation towards CD8+ T and NK cells, while limiting interaction with Tregs. Tang teaches mutations including substitutions in R38 and F42, as well as combination sets including R38D, K43E, E61R, and R38A, F42A, Y45A, and E62A and teaches that these mutations result in reductions in CD25 binding. In contrast, Tang teaches a number of mutations that can enhance CD25 binding, such as V69A and Q74P. Different combinations of these mutations yielded affinities that could approach 1000 times that of WT IL2 (page 3, 3.1.1). With regards to CD122 binding, Tang teaches that most strategies target the IL2-CD25 interaction do so by altering residues directly involved at the binding interface, but that for CD122, changing amino acids outside of the CD122 binding interface has been shown to change the conformation sufficiently to more closely resemble its high affinity receptor-bound state. This results in a molecule that could bind CD122 with ~200 fold higher affinity and could stimulate intermediate affinity receptors with 10x higher potency than WT IL2 (page 3, 3.1.2.).
The teachings of Tang demonstrate that even a few specific changes in IL2 can have profound effects on function and toxicity. Tang demonstrates that certain mutations in certain places can cause increases in IL2 interaction with the native IL2 receptors while others can decrease interaction. Tang also demonstrates that mutations in positions even outside of the binding residues can impact conformation and binding of IL2.
Sockolosky, J.T., et al (2018) Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes Science 359(6379); 1037-1042 teaches the engineering of IL-2 cytokine receptor orthogonal (ortho) pairs that interact with one another transmitting native IL-2 signals, but do not interact with their natural cytokine and receptor counterparts (abstract). Sockolosky created an ortholog, double mutant, IL-2RB receptor that lacked detectable binding to IL-2, even in the presence of CD25 (paragraph bridging pages 2-3). Sockolosky then used yeast display-based evolution to mutate, and thus remodel, the wild-type IL-2 interface region that was opposing (or facing the site of) the IL-2RB mutations in the crystal structure, in order to create a molecule that bound to orthoIL-2RB but not to wild-type IL-2RB. IL-2 residues were randomly mutated and chosen on the basis of a homology model of the mouse IL-2/IL-2RB complex derived from the crystal structure of the human IL-2 receptor complex. A
library of ~108 unique IL-2 mutants was displayed on the surface of yeast (fig. S2) and subjected to multiple rounds of both positive (against orthoIL-2Rβ) and negative (against IL-2Rβ) selection. A consensus of mutations were then identified and molecular interactions were studied after which two mutant candidates were selected (page 3, paragraphs 2-4).
The teachings of Sockolosky demonstrates that there are a significant number of IL2 mutations that can be made and identified for the production of orthogonal IL2 polypeptide; however, trial and error experimentation and analysis is required in order to identify orthogonal IL2 polypeptides that bind effectively to an orthogonal IL2RB receptor.
The teachings of Tang and Sockolosky suggest that the structure-function correlation between orthogonal IL2 and binding was not predictable as even single mutations, not even at the binding interface, can result in significant changes in function.
Neither the disclosure, nor the prior art, provide a representative number of species of the claimed genus performing the claimed function. The disclosure and art also do not provide a structure-function correlation that could be used to identify which species of the instantly claimed genus would be capable of performing the claimed functions. As such, the instant claim was found not to meet the written description requirement of 35 USC 112(a).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-4, 12, 14, and 19-22 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018.
US’842 teaches engineered cytokines and receptors that enhance selective expansion of desired cell subsets in settings of ex vivo adoptive cell therapy. The examples provided are specific for the cytokine IL-2 and its receptor the IL-2Rβ chain, which enables the specific expansion of T cells in adoptive cell therapy. US’842 exemplifies orthologous IL-2 and orthologous IL-2Rβ (page 13, [0129]). US’842 also teaches that IL-2Rβ is also known as CD122 (page 10, [0097]).
US’842 teaches methods for enhancing cellular responses by engineering cells from a recipient or donor by introduction of an orthologous receptor by contacting the engineered cell with the cognate orthologous receptor. The subject methods include a step of obtaining the targeted cells which may be isolated from a biological sample, or may be derived from progenitor cells. The cells are then transduced or transfected with an expression vector comprising a sequence encoding the orthologous receptor, which step may be performed in any suitable culture medium (page 10, [0106]).
US’842 further teaches that the recipient is mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans (page 8, [0083]).
US’842 further teaches that the engineered cell is a T cell, including without limitation naïve CD8+ T cells, helper T cells, e.g., TH1, TH2, TH9, TH11, TH22, TFH; regulatory T cells, e.g., TR1, natural Treg, inducible Treg; memory T cells, e.g., central memory T cells, effector memory T cells, NKT cells, γδT cells, etc. In other embodiments, the engineered cell is a stem cell or an NK cell (page 11, [0106]).
US’842 also teaches a therapeutic method comprising introducing into a recipient in need thereof an engineered cell population, wherein the cell population has been modified by introduction of a sequence encoding an orthologous receptor. The cell population is modified ex vivo and is usually autologous or allogeneic with respect to the recipient. In some embodiments, the introduced cell population is contacted with the cognate orthologous cytokine in vivo following administration of the engineered cells. An advantage of the orthologous receptors/ligands is a lack of cross reactivity between the orthologous cytokine and the native receptor (page 11, [0108]). US’842 further teaches that, when the cells are contacted with the orthologous cytokine in vitro, the cytokine is added to the engineered cells in a dose and for a period of time sufficient to activate signaling from the receptor, which may utilize the native cellular machinery, e.g., accessory proteins, co-receptors, and the like. The cells thus activated may be used for any desired purpose, including for in vivo delivery (page 11, [0109]). US’842 further teaches administration of an effective dose of the engineered cells in combination with, or prior to, the orthologous cytokine. Dosages and frequency may vary depending on the agent and will be adjusted for individual circumstances. Generally, at least about 104 engineered cells/kg, at least about 105 cells/kg, at least 106 cells/kg, or at least 107 cells/kg are administered (page 11, [0110]). Where the engineered cells are T cells, an enhanced immune response may be manifested as an increase in the cytolytic response of T cells towards the target cells present in the recipient, e.g., towards the target cells present in the recipient, e.g. towards elimination of the tumor cells, infected cells, decreased symptoms of autoimmune disease, and the like (page 11, [0011]).
US’842 exemplifies the production and evolution of IL-2Rβ orthogonal receptors and ligands (pages 14-15). US’842 further demonstrates a method in which PBMCs were retrovirally transduced with an orthogonal human IL-2Rβ receptor (pages 14-17). In the example, leukoreduction chambers were acquired from the Stanford Blood Center and PBMC were isolated from the blood. The cells were then activated with human T-activator CD3/CD28 and hIL-2 and incubated. Activated human PBMCs were then transduced via spinfection using unconcentrated retroviral supernatant.
US’842 further studied the in vitro primary human PBMC proliferation of the cells (page 16, [0171]-[0173]). In the study, human PBMC containing a mixture of the wild-type and ortho transduced T cells were collected by centrifugation and cell growth was stimulated by the addition of serial dilutions of wild-type or orthoIL-2 for two days. US’842 provides the total live cell count plotted vs. the concentration of cytokine or as a ratio of ortho cells to total live cells plotted vs. the concentration of cytokine.
As shown in Fig. 22, ortho human IL-2 signals through the orthoIL-2R expressed in YT cells in vitro. As shown in Fig. 23, ortho human IL-2 preferentially expands human PBMCs expressing the ortho-IL-2R. US’842 teaches that human PBMC were isolated, activated, and transformed with retrovirus containing ortho human IL-2RB with an IRES YFP (YFP+). The initial ratio of YFP+ cells to total live cells was 20%. 5x105 cells were plated with the indicated concentrations of MSA-human IL-2 or ortho variants MSA-SQVLKA, MSA-SQVLqA, or MSA-1A1 on day 1 and re-fed the same concentration on day 3. On day 5, the plate was read by flow cytometry. The ratio of YFP+ ortho expressing cells to total live cells was calculated and plotted versus concentration. The orthogonal cytokines did not support as much total cell growth as wild-type MSA-hIL-2 at the same concentration, but were selective in strongly expanding the ortho-expressing T cells (page 16, [0173]).
US’842 further teaches in vivo mouse models used to demonstrate selective expansion or increased survival of orthogonal IL-2Rb expressing T cells in mice. Donor cells were isolated from the spleen of wild-type mice and activated ex vivo with CD3/CD28, transduced with retrovirus encoding orthogonal IL-2Rb-IRES-YFP, expanded for two days in 100 IU/mL mIL-2, and purified using a mouse CD8 T cell isolation kit. A 1:1 mixture of wild-type and orthogonal IL-2RB expressing cells were adoptively transferred into the recipient. Mice were then injected with PBS, wild-type IL-2, or ortho IL-2 daily beginning immediately after T cell transfer and at 24 hr intervals for 5 consecutive days up to d4. Mice were sacrificed on d5 and d7 and total donor T cell counts were quantified (page 2, [0028]; Fig. 17). The results show that the orthoIL-2 clone selectively expanded orthogonal but not wild-type T cells in mice (page 2, [0028]; Figs. 18-20).
US’842 further demonstrates that the orthologous protein is expressed from a nucleic acid that is inserted into the vector for expression (page 6, [0063]).
US’842 teaches that the orthogonal receptor is CD122 and that positions of interest for substitution or deletion include, without limitation, in human CD122 (hCD122) R41, R42, Q70, K71, T73, T74, V75, S132, H133, Y134, F135, E136, Q214 (page 10, [0098]). US’842 also exemplifies the orthogonal IL-2 engineering approach in human IL-2 and human IL-2RB in which H133D and Y134F mutations were used and teaches that the hIL-2RB H133D Y134F mutant lacks detectable binding to wild-type IL-2 (page 14, [0146]). The orthogonal human IL-2RB receptor with H133D and Y134F modification is provided by US’842 as SEQ ID NO: 9 in which the modifications are made in the wild-type human IL-2RB of SEQ ID NO: 1 (page 2, [0026]; pages 23-24). The receptor disclosed is a transmembrane receptor that comprises an intracellular signaling domain of IL-2RB in operable communication with the extracellular domain which has been modified to be an orthogonal IL-2RB.
US’842 further teaches the methods disclosed for the treatment of neoplastic conditions, such as cancer; infections, including chronic pathogen infections, including viral infections; and autoimmune diseases and inflammatory diseases (pages 8-9, [0087]-[0092]; page 12, [0122]-[0126]).
While US’842 does not exemplify the method of treating or preventing a disease, disorder, or condition in a mammalian subject, US’842 teaches methods of making cells engineered to express an orthogonal hCD122 that meets the limitations of instant claim 1, (a)-(c) and further teaches methods in which diseases, disorders, conditions are treated by administration of the cells and a therapeutically effective dose of an orthogonal ligand that binds to the orthogonal receptor. As such, it would have been prima facie obvious prior to the effective filing date of the claimed invention to apply the methods of US’842 in a method of treating or preventing the diseases, disorders, or conditions disclosed with a reasonable expectation of success.
Regarding claim 12, while US’842 does not explicitly disclose that the orthogonal ligand in the ex vivo step is different than that used in the in vivo step, US’842 teaches multiple orthogonal ligand variants, including MSA-SQVLKA, MSA-SQVLqA, or MSA-1A1, that bind to the orthogonal IL-2RB receptor. As such, it would have been obvious to use any of these ligands for the ex vivo or in vivo step which encompasses combinations in which the orthogonal ligand is different in each step. An ordinarily skilled artisan would have had a reasonable expectation of success as US’842 demonstrates that each of these ligands is capable of binding the orthogonal receptor resulting in signaling. Additionally, US’842 teaches that orthogonal IL2 can be fused to the Fc domain of IgG, albumin, or other molecules to extend its half-life, e.g., by pegylation, glycosylation, and the like as known in the art, and that such fusion can endow alternative Fc receptor mediated properties in vivo. Teachings which demonstrate alternative orthogonal IL2 ligands for administration.
Claims 1-14, 19-22, 25-29, 32, 34, 42-46, and 48-50 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 in view of US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018.
US’533 teaches inducible chimeric cytokine receptors responsive to a ligand, e.g., a small molecule or a protein and uses of such receptors for improving the functional activities of genetically modified immune cells, such as T cells, comprising the inducible chimeric cytokine receptors (abstract). US’533 further teaches that the T cells are gene modified antigen-specific T cells, such as chimeric antigen receptor T (CAR-T) cells and that the addition of the inducible chimeric cytokine receptor bolsters the therapeutic efficacy of CAR-T cells (page 1, [0006]).
US’533 teaches a method of generating an engineered immune cell comprising the steps of (a) providing an immune cell; (b) introducing into the immune cell a polynucleotide that encodes a chimeric antigen receptor (CAR) comprising an extracellular ligand-binding domain, a transmembrane domain, and an intracellular signaling domain; and (c) introducing into the immune cell a polynucleotide that encodes the inducible chimeric cytokine receptor (pages 91-92, claim 79). US’533 further teaches a method for treating a subject comprising administering a pharmaceutical composition comprising the engineered cell to a subject (page 92, claim 89).
US’533 further claims that the engineered immune cell is an autologous cell (page 3, [0047]) and an isolated immune cell (page 3, [0050]) indicating that it is isolated from the subject being treated. US’533 teaches that, in an exemplary embodiment, the immune cell is selected from the group consisting of T cell, dendritic cell, killer dendritic cell, mast cell, NK-cell, macrophage, monocyte, B-cell, and an immune cell derived from a stem cell (page 3, [0049]). US’533 also teaches that the cells can be obtained from sources including PBMC and tumors (page 66, [0293]). US’533 further teaches that the subject is a mammal, and, in exemplary embodiments, the subject is a human (pages 9-10, [0210]).
US’533 further teaches a method in which CAR T cell manufacturing is improved by replacing high doses of supplemental cytokines, which would expand both the transduced CAR+ and untransduced CAR- T cells in the same culture, with the ligand that activates the inducible cytokine receptor. US’533 also teaches that, on day 0, purified T cells are activated and, on day 2, T cells are suspended in T cell transduction media, suggesting activation of the cells after isolation but before transduction (page 85, Example 13).
US’533 teaches that the isolated immune cell exhibits improved persistence upon contact with a ligand that binds to the dimerization domain of the inducible chimeric cytokine receptor relative to persistence of an isolated immune cell that does not express the inducible chimeric cytokine receptor (page 3, [0052]).
US’533 further teaches that the CAR comprises an extracellular ligand binding domain, e.g., a single chain variable fragment (scFv), a transmembrane domain, and an intracellular signaling domain. US’533 teaches that the extracellular ligand-binding domain of the CAR binds to a target of interest including, for example, BCMA, EGFRvIII, FLT3, WT-1, CD20, CD30, CD70, CD33, ROR1, CD19, FAP alpha, and CD44v6 (page 64, [0281]).
US’533 further teaches that the intracellular signaling domain of the CAR can be the cytoplasmic sequences of, for example, the T cell receptor and co-receptors that act in concert to initiate signal transduction following antigen receptor engagement, as well as any derivative or variant of these sequences and any synthetic sequences that have the same functional capability. Intracellular signaling domains comprise two distinct classes of cytoplasmic signaling sequences: those that initiate antigen dependent primary activation, and those that act in an antigen independent manner to provide a secondary or co-stimulatory signal. Primary cytoplasmic signaling sequences can comprise signaling motifs which are known as immunoreceptor tyrosine-based activation motifs or ITAMs. ITAMs are well defined signaling motifs found in the intracytoplasmic tail of a variety of receptors that serve as binding sites for syk/zap70 class tyrosine kinases. Examples of ITAM used in the invention can include those from TCRζ, FcRγ, FcRβ, CD3γ, CD3δ, or CD3ε (page 64, [0284]). US’533 further teaches that the CAR can comprise a co-stimulatory domain from 4-1BB and CD28 (page 64, [0285]).
US’533 further teaches that the inducible chimeric cytokine receptor can comprise the IL2Rb distal cytotail for signaling (page 14, [0252]).
US’533 further teaches that, to direct transmembrane polypeptides into the secretory pathway of the host cell, a secretory signal sequence (also known as a leader sequence) is provided in a polynucleotide sequence or vector sequence. The signal sequence is operably linked to the transmembrane nucleic acid and directs the synthesized polypeptide to the secretory pathway of the host cell (page 69, [0319]).
US’533 further teaches expression vectors comprising the recombinant polynucleotides comprising an expression control sequence operatively linked to a nucleotide sequence to be expressed. Expression vectors include all of those known in the art, including lentiviruses and adenoviruses that incorporate recombinant polynucleotide (page 7, [0189]). US’533 teaches that the inducible chimeric cytokine receptor or a CAR may exist in an expression cassette or vector (page 68 [0317]) and that vectors containing the polynucleotides can be introduced into the host ell by any number of appropriate means, including electroporation, transfection, microprojectile bombardment, lipofection, and infection (page 68, [0316]). US’533 also teaches that the polynucleotide sequence or vector can include a nucleic acid sequence encoding a ribosomal skip sequence such as, for example, a 2A peptide. Such ribosomal skip sequences are well known in the art and are known to be used by several vectors for the expression of several proteins encoded by a single messenger RNA (page 68, [0318]). US’533 further exemplifies a lentiviral construct that comprises an inducible chimeric cytokine receptor, a T2A sequence, and a CAR (page 80, [0451]).
US’533 teaches that the methods can further comprise administering one or more therapeutic agents to a subject prior to administering the engineered immune cells bearing a CAR and inducible chimeric cytokine receptor. In certain embodiments, the agent is a lymphodepleting (pre-conditioning) regimen (page 70, [0330]).
US’533 further teaches that the immune cells, such as an isolated T cell, disclosed can be used in the manufacture of a medicament for the treatment of a disorder including a cancer, autoimmune disorder, or an infection (page 70, [0327]).
The teachings of US’533 differ from the instantly claimed invention in that US’533 does not disclose that the inducible cytokine receptor is an orthogonal hCD122 receptor or that the ligand is an orthogonal ligand.
The teachings of US’842 are as discussed in detail above.
As discussed above, US’842 teaches that the orthogonal human IL-2RB receptor has a H133D and Y134F modification, which is presented in SEQ ID NO: 9. In SEQ ID NO: 9, the modifications are made in the wild-type human IL-2RB of SEQ ID NO: 1 (page 2, [0026]; pages 23-24). The receptor disclosed is a transmembrane receptor that comprises the transmembrane and intracellular signaling domain of IL-2RB in operable communication with the extracellular domain which has been modified to be an orthogonal IL-2RB.
US’842 SEQ ID NO: 9 is a species of instant SEQ ID NO: 53, as recited in instant claim 25, as shown in the alignment below:
PNG
media_image1.png
289
583
media_image1.png
Greyscale
US’842, SEQ ID NO: 9 reads on instant SEQ ID NO: 53, where AA70 is Gln (Q); AA73 is Thr (T); AA133 is Asp (D); and AA134 is Phe (F).
US’842 further teaches that the orthogonal IL-2 can be fused to the Fc domain of IgG, albumin, or other molecules to extend its half-life, e.g., by pegylation, glycosylation, and the like as is known in the art (page 5, [0049]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the methods of US’533 with the methods of US’842 to arrive at the instantly claimed invention by substituting the inducible chimeric cytokine receptors and ligands disclosed by US’533 with the orthogonal IL-2RB (CD122) receptor and orthogonal hIL-2 ligands disclosed by US’842. It would have been obvious to make this substitution, and the results would have been predictable, as both US’533 and US’842 are teaching inducible cytokine receptors for use in immune cells, such as T cells, for use in adoptive cell therapy in which the cytokine receptor is activated by the administration of an exogenous peptide, such as a ligand. An ordinarily skilled artisan would have further had a reasonable expectation of success because US’533 teaches that the inducible chimeric cytokine receptors disclosed can comprise a signaling domain from a cytokine, including IL2Rb, suggesting the use of the same signaling.
Regarding claim 12, while the combination of US’533 and US’842 does not explicitly disclose that the orthogonal ligand in the ex vivo step is different than that used in the in vivo step, US’842 teaches multiple orthogonal ligand variants, including MSA-SQVLKA, MSA-SQVLqA, or MSA-1A1, that bind to the orthogonal IL-2RB receptor. As such, it would have been obvious to use any of these ligands for the ex vivo or in vivo step which encompasses combinations in which the orthogonal ligand is different in each step. An ordinarily skilled artisan would have had a reasonable expectation of success as US’842 demonstrates that each of these ligands is capable of binding the orthogonal receptor resulting in signaling. Additionally, US’842 teaches that orthogonal IL2 can be fused to the Fc domain of IgG, albumin, or other molecules to extend its half-life, e.g., by pegylation, glycosylation, and the like as known in the art, and that such fusion can endow alternative Fc receptor mediated properties in vivo. Teachings which demonstrate alternative orthogonal IL2 ligands for administration.
Regarding claims 26, 29, and 48, the extracellular domain of the orthogonal receptor taught by US’842 comprises instant SEQ ID NO: 6, as is recited in instant claim 26, as shown in the ABSS alignment below:
PNG
media_image2.png
289
579
media_image2.png
Greyscale
US’842, SEQ ID NO: 9 also has a sequence of instant SEQ ID NO: 7, as recited in instant claim 29, as shown in the alignment below:
PNG
media_image3.png
587
578
media_image3.png
Greyscale
US’842 also discloses human IL-2 of SEQ ID NO: 4, which is identical to instant SEQ ID NO: 50, as recited in instant claim 48, when all of the variable amino acids are wild type, as shown in the ABSS alignment below:
PNG
media_image4.png
231
586
media_image4.png
Greyscale
US’842 exemplifies ortho variants including MSA-SQVLKA, MSA-SQVLqA, and MSA-1A (page 16, [0173]), which comprise the mutations shown in Table 1.
SQVLKA meets the limitations of instant SEQ ID NO: 50, where AA15 is S; AA16 is Q; AA19 is V; AA20 is L; AA22 is K; and AA23 is A and all other amino acids are wild-type;
SQVLqA meets the limitations of instant SEQ ID NO: 50, where AA15 is S; AA16 is Q; AA19 is V; AA20 is L; and AA23 is A and all other amino acids are wild-type; and
1A1 meets the limitations of instant SEQ ID NO: 50, where AA15 is S; AA16 is Q; AA19 is V; AA20 is L; AA23 is Q; AA51 is I and R81 is D and all other amino acids are wild-type.
Regarding claim 49, US’842 further teaches orthogonal human IL-2 in which one or more of the following amino acid residues are substituted with an amino acid other than that of the native protein, or are deleted in that position: of Q13, L14, E15, H16, L19, D20, Q22, M23, G27, R8I, or N88. US’842 also teaches substitutions for hIL-2 including one or more of: [Q13W], [L14M, L14W], [E15D, E15T, E15A, E15S], [H16N, H16Q], [L19V, L19I, L19A], [D20L, D20M], [Q22S, Q22T, Q22E, Q22K, Q22E], [M23A, M23W, M23H, M23Y, M23F, M23Q, M23Y], [G27K, G27S], [R81D, R81Y], and [N88E, N88Q]. US’842 also teaches the mutation [T51I] (page 10, [0101]-[0102]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to try combinations of these modifications for the orthogonal hIL-2 in the methods taught by the combination of US’533 and US’842 which encompass the instantly claimed modification set of E15D, H16N, L19V, D20L, Q22K, and M23A. An ordinarily skilled artisan would have been capable of pursuing these finite number of known mutation combinations with a reasonable expectation of success as US’842 identifies these amino acid positions and substitutions in wild-type IL-2 as a means to produce an orthogonal hIL-2 for use with the orthogonal IL-2RB receptor.
Claims 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 in view of US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as applied to claim 1 above, and in further view of EP 3 126 380 B1 (Pule, M., et al) 08 Feb 2017.
The combination of US’533 and US’842 teach the method of claim 1 as discussed in detail above.
US’533 further provides examples in which the inducible chimeric cytokine receptor was activated with ligand the day after T cell infusion and weekly thereafter. Tumors were then monitored every 2-3 days until the end of the study (page 83, [0480]). Results are reported in Fig. 31F-H in which it is shown that the studies continued for 60+ days and survival was significantly higher/longer compared to controls.
The combination of applied references, however, do not disclose the recited regimens for the administration of the orthogonal ligand.
EP’380 teaches an inducible CAR system, where signaling only takes place in the presence of an agent, such as a small molecule, that induces dimerization (page 4, [0013]).
EP’380 further teaches methods of treating diseases including cancer (page 6, [0053]). EP’380 teaches that the method may involve monitoring the progression of the disease and/or toxic activity and adjusting the dose of the chemical inducer of dimerization (CID) to provide acceptable levels of disease progression and/or toxicity (page 6, [0052]). EP’380 teaches a means of tuning the CAR activity to the presence of an agent, such as a small molecule, and teaches that this allows the potency of the CAR to be controlled pharmacologically and tuned to an acceptable balance between achieving the desired therapeutic effect, while avoiding CAR-associated toxicities (page 7, [0065]). EP’380 further teaches that the signaling system can be reduced by reducing or stopping administration of the CID to the subject. Alternatively, signaling may be activated by administering the CID (page 6, [0060]-[0063]; page 10, [0094]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of US’533 and US’842 by monitoring the progression of the disease and/or toxic activity and adjusting the dose of the orthogonal ligand in order to achieve acceptable levels of disease progression and/or toxicity as taught by EP’380 to arrive at the instant claims. An ordinarily skilled artisan would have been motivated to adjust the administration of the orthogonal ligand in order to optimize treatment based on progression of the disease and/or toxicity. An ordinarily skilled artisan would have had a reasonable expectation of success as, like US’533 and US’842, EP’380 teaches methods of using CAR T cells to treat diseases such as cancer using inducible elements that allow for the control of cell activation and proliferation. Additionally, EP’380 demonstrates that modulation by increasing administration or stopping administration of an inducing element had been considered in the art. Specifically, EP’380 teaches that administering the ligand induces activation/proliferation of the cells and stopping administration of the ligand reduces or stops activation/proliferation of the cells.
Furthermore, the determination of the optimal timing or amounts is considered to be routine optimization when the art had considered the impacts of such elements. MPEP 2144.05 (II) A. states that "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”.
In this case, US’842 teaches that the cells are administered at dosages which include 105 and 106 engineered cells/kg and teaches that the engineered cells increase the cytolytic response of the T cells towards elimination of tumor cells (page 11, [0111]); US’533 demonstrates administration of an inducing ligand to a chimeric cytokine receptor periodically over more than two weeks; and EP’380 demonstrates monitoring and adjusting ligand dosage as a means to modulate the activation/proliferation of inducible CAR T cells in an effort to optimize disease treatment. It would have been obvious to use these teachings and optimization that was known and practiced in the art in order to arrive at the instantly claimed invention.
Claims 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 in view of US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as applied to claims 25-29 above, and in further view of US 2018/0037630 A1 (Tanaka, S., et al) 8 Feb 2018.
The combination of US’533 and US’842 teach the orthogonal mammalian CAR T cell of claim 29 as discussed in detail above.
US’533 further teaches that the isolated immune cell disclosed exhibits increased activation of STAT upon contact with a ligand that binds to the dimerization domain relative to activation of STAT, including STAT3, shown by an isolated immune cell that does not express the inducible chimeric cytokine receptor (page 3, [0053]).
The combination of applied references, however, do not disclose that the intracellular domain of the receptor further comprises at least one STAT3 signaling motif as recited in claims 30-31.
US’630 teaches that STAT3, or signal transducer and activator of transcription 3, refers to a transcription factor belonging to the STAT protein family. The STAT3 protein is involved in regulating genes that are involved in cell growth and division, cell movement, and cell apoptosis. In the immune system, STAT3 is a signal transducer for the maturating of the immune system cells such as T cells and B cells. It has been shown that STAT3 plays a role for the development and maintenance of human T cell memory (page 3, [0067]). US’630 further teaches STAT3 associated motifs referring to an amino acid sequence of YXXQ, which binds STAT3. The STAT3 association motif is present in signaling proteins, for example IL-6 and IL10. The STAT3 association motif can also be introduced into signaling domains that do not endogenously comprise the STAT3 association motif. For example, a YXXQ exogenous STAT3 association domain can be introduced. US’630 further teaches YRHQ and teaches that the STAT3 association motif can be introduced using various techniques understood in the art (page 3, [0068]). US’630 further teaches that the X in the STAT3 association motif YXXQ can be any naturally occurring amino acid that retains STAT3 binding. In one embodiment, X is independently chosen from leucine, arginine, histidine, phenylalanine, lysine, praline, methionine, valine, glutamine, threonine or aspartate (page 7, [0117]). While the STAT3 association motif may be introduced at any portion of the intracellular signaling domain, US’630 teaches that studies have shown that a YXXQ motif located near the C-terminus region has been shown to be more functional (page 7, [0118]-[0119]). Other STAT3 association motifs are also known in the art and include, for example, YLRQ, YFKQ, YLPQ, YLKQ, and YMPQ (page 8, [0138]). US’630 further teaches that the intracellular segment may comprise multiple STAT3 association motifs which may be introduced into any of the intracellular signaling domains (page 9, [0139]-[0140]).
US’630 exemplifies CARs comprising an IL2RB cytoplasmic domain with a STAT3 (YXXQ) motif and teaches that the addition of these domains led to superior proliferation through higher cell division and reduced apoptosis compared to control CAR T cells without IL2RB and the STAT3 motif. Additionally, the T cells comprising the IL2RB and STAT3 signaling domains also maintained a stem cell-like memory phenotype after repeated antigen stimulation (page 13, [0200]). US’630 also teaches that in studies with CD19 CAR T cells, CARs comprising the signaling domains showed decreased tumor activity as well as increases in overall survival compared to untreated mice or control CAR T cells (page 13, [0201]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR T cell taught by the combination of US’533 and US’842 by further including at least one STAT3 signaling domain as taught by US’630. An ordinarily skilled artisan would have been motivated to further include a STAT3 as US’630 demonstrates that signaling domains that further comprise the STAT3 signaling motifs provide superior proliferation though higher cell division and reduced apoptosis as well as decreased tumor activity and increases in overall survival. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533 and US’842, US’630 is teaching the treatment of diseases, such as cancer, using CAR T cells. Additionally, US’630 teaches the use of the cytoplasmic domain of IL2RB, which is the same domain taught by US’842.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 in view of US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as applied to claims 25 and 32 above, and in further view of WO 2017/028374 A1 (Yonghao, Y., et al) 23 Feb 2017.
The combination of US’533 and US’842 teach the orthogonal mammalian CAR-T cell of claim 32 as discussed in detail above.
As discussed above, US’533 teaches that the CAR can bind to CD19. US’533 further teaches that, to direct transmembrane polypeptides into the secretory pathway of the host cell, a secretory signal sequence (also known as a leader sequence) is provided in a polynucleotide sequence or vector sequence. The signal sequence is operably linked to the transmembrane nucleic acid and directs the synthesized polypeptide to the secretory pathway of the host cell (page 69, [0319]).
The combination of US’533 and US’842; however, do not disclose that the CAR that binds to CD19 comprises one of the sequences recited in instant claim 37.
WO’374 teaches a construct carrying a sequence encoding a full length costimulatory molecule and a chimeric antigen receptor, as well as genetically modified lymphocytes generated by introducing the construct. The construct and genetically modified lymphocytes may be used in adoptive cell therapies. WO’374 teaches that the CAR comprises an ectodomain comprising a heavy and light chain variable region of a single-chain antibody binding to the antigen CD19; a transmembrane domain linked to the ectodomain and embedded in a cellular membrane of the T cell; and an endodomain linked to the transmembrane domain comprising intracellular domains of CD28 and the ζ-chain of CD3 (page 1, line 32-page 2, line 12). WO’374 teaches that the CD19 specific CAR comprises a sequence of SEQ ID NO: 2 (page 2, line 24-page 3, line 1), which is identical to instant SEQ ID NO: 30, as shown in the ABSS alignment below:
PNG
media_image5.png
402
618
media_image5.png
Greyscale
PNG
media_image6.png
401
614
media_image6.png
Greyscale
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of US’533 and US’842 by using the CD19 targeting CAR sequence disclosed by WO’374 as the CAR that targets CD19. An ordinarily skilled artisan would have been able to make this substitution with a reasonable expectation of success because both CARs target the same antigen, CD19, and are taught for expression in immune cells, including T cells, for use in adoptive cell therapy. Furthermore, US’533 teaches that the CAR can comprise a signal peptide, a CD19 scFv, a transmembrane domain, co-stimulatory domain from CD28 and an intracellular signaling domain from TCRζ (which is the ζ chain of CD3), demonstrating the same types of domains as those presented in the CD19 CAR of WO’374.
Claims 33 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 in view of US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as applied to claim 25 above, and in further view of US 2018/0022815 A1 (Chang, L.) 25 Jan 2018, WO 2018/161017 (Suri, V., et al) 07 Sept 2018 and US 2018/0265585 A1 (Seogkyoung, K.) 20 Sept 2018.
The combination of US’533 and US’842 teach the orthogonal mammalian CAR-T cell of claim 25 as discussed in detail above.
As discussed above, US’533 teaches that the CAR comprises an extracellular signaling domain, a transmembrane domain, co-stimulatory domain, and an intracellular signaling domain. US’533 further teaches that the transmembrane domain can comprise a hinge, or stalk, domain from human CD8a (page 64, [0286]). US’533 teaches that the co-stimulatory domain can be from CD28 and the ITAM can be derived from TCRζ. US’533 further teaches that, to direct transmembrane polypeptides into the secretory pathway of the host cell, a secretory signal sequence (also known as a leader sequence) is provided in a polynucleotide sequence or vector sequence. The signal sequence is operably linked to the transmembrane nucleic acid and directs the synthesized polypeptide to the secretory pathway of the host cell (page 69, [0319]).
The combination of US’533 and US’842; however, do not disclose that the CAR that binds to PSMA or comprises one of the sequences recited in instant claim 38.
US’380 teaches compositions comprising a cell that comprises nucleic acids encoding a CAR and one or more signaling proteins, wherein the CAR comprises an extracellular specific domain, a transmembrane domain, and an intracellular signaling domain comprising an immunoreceptor tyrosine-based activation domain (ITAM). US’380 further teaches that the CAR comprises one or more co-stimulatory domains. Also provided are methods for treating diseases using the compositions (abstract).
US’380 teaches that the CAR can target antigens specific for disease, including PSMA (page 35, [270); page 48, [0497]).
US’380 teaches a CAR that targets PSMA comprising SEQ ID NO: 3427, which comprises a CD8 signal peptide, PSMA-J591 (VL-VH),-myc-BBz-T2A-PAC (page 101, Table 21, second PSMA CAR).
US’380, SEQ ID NO: 3427 has the following alignment with instant SEQ ID NO: 43:
PNG
media_image7.png
823
611
media_image7.png
Greyscale
As shown in the alignment above, the PSMA targeting CAR of US’380 comprises the same signal peptide and heavy and light chain variable regions as those claimed in instant claim 43. The CAR also comprises the same 4-1BB costimulatory domain. The PSMA CAR of US’380 differs from the instantly claimed PSMA CAR in the linker that is used to join the heavy and light chain variable regions, the presence of a myc domain, the hinge and transmembrane domain, and an additional Q amino acid in the CD3 zeta signaling domain.
US’380 further teaches immune effector cells, including T cells or NK cells, engineered to express a CAR, where the engineered immune cell exhibits an anticancer property (page 45, [0451]).
US’815 teaches linkers that can be used in the production of CARs including (GGGGS)x3 and GSTSGGGSGGGSGGGGSS (SEQ ID NO: 6) (page 4, [0044]).
The substitution of the alternative linker taught by US’815 in place of the (G4S)3 linker disclosed by US’380, results in a signal peptide and scFv region that is identical to instant SEQ ID NO: 43, amino acids 1-261, as shown in the alignment below:
PNG
media_image8.png
350
573
media_image8.png
Greyscale
WO’017 teaches CARs and commonly used CAR domains.
WO’017 teaches a CD8a hinge region of SEQ ID NO: 437 (page 68), which is identical to instant SEQ ID NO: 43, AA 262-306, as shown in the ABSS alignment below:
PNG
media_image9.png
114
581
media_image9.png
Greyscale
WO’017 also teaches a CD8a transmembrane domain of SEQ ID NO: 413 (page 66), which is identical to instant SEQ ID NO: 43, AA 307-327, as shown in the alignment below:
PNG
media_image10.png
109
583
media_image10.png
Greyscale
WO’017 also teaches the 4-1BB intracellular signaling domain of SEQ ID NO: 273 (page 75), which is identical to instant SEQ ID NO: 43, AA 328-369, as shown in the ABSS alignment below:
PNG
media_image11.png
111
582
media_image11.png
Greyscale
US’585 teaches chimeric antigen receptors and CAR-T cells in which the receptor is expressed, the CAR comprising an antigen binding domain; a hinge region; a transmembrane domain; a costimulatory domain; and a cytoplasmic signaling domain. US’585 further teaches that the cytoplasmic signaling domain comprises a CD3z signaling domain of a human, where an extra glutamine is comprised, not a CD3z signaling domain of a Jurkat T cell (page 2, [0015]). US’585 teaches that the CD3z has an extra glutamine in the 50th position of SEQ ID NO: 13 (page 4, [0044]). US’585, SEQ ID NO: 13, is identical to instant SEQ ID NO: 43, amino acids 370-482, as shown in the ABSS alignment below:
PNG
media_image12.png
167
585
media_image12.png
Greyscale
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of US’533 and US’842 by substituting the CAR with a PSMA targeting CAR comprising the signal peptide and heavy and light chain variable regions disclosed by US’380. It would have further been obvious to substitute the linker in the PSMA CAR with the alternative linker disclosed by US’815, to use the CD8a hinge, transmembrane domain, and 4-1BB costimulatory domain taught by WO’017, and to use the CD3z intracellular signaling domain disclosed by US’585. It would have been obvious to substitute the CAR with a CAR targeting PSMA as US’380 demonstrates that the PSMA targeting CARs had been studied in the art for expression in T cells for applications in treating cancer. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533, US’380 is teaching methods of treating cancer using CAR T cells. It would have been obvious to substitute the domains of the CAR with the alternatives disclosed by US’815, WO’017, and US’585 as the references teach alternative amino acid sequences for the same domains for use in CAR T cell production. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 in view of US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as applied to claims 25 and 34 above, and in further view of WO 2018/140725 A1 (Posey, A.D. and S. Guedan Carrio) 02 Aug 2018.
The combination of US’533 and US’842 teach the orthogonal mammalian CAR-T cell of claim 34 as discussed in detail above.
As discussed above, US’533 teaches that the CAR can bind to BCMA. US’533 further teaches that, to direct transmembrane polypeptides into the secretory pathway of the host cell, a secretory signal sequence (also known as a leader sequence) is provided in a polynucleotide sequence or vector sequence. The signal sequence is operably linked to the transmembrane nucleic acid and directs the synthesized polypeptide to the secretory pathway of the host cell (page 69, [0319]).
The combination of US’533 and US’842; however, do not disclose that the CAR that binds to BCMA comprises one of the sequences recited in instant claim 39.
WO’725 teaches CARs comprising antigen binding domains that bind tumor antigens including BCMA (page 7, lines 20-26; page 73, lines 29-31; pages 153-210). WO’725 further teaches exemplary sequences for BCMA CARs including SEQ ID NO: 977 (page 156; 139103-aa full CAR), which is identical to instant SEQ ID NO: 34, as shown in the alignment below:
PNG
media_image13.png
824
619
media_image13.png
Greyscale
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of US’533 and US’842 by using the BCMA targeting CAR sequence disclosed by WO’725 as the CAR that targets BCMA. An ordinarily skilled artisan would have been able to make this substitution with a reasonable expectation of success because both CARs target the same antigen, BCMA, and are taught for expression in immune cells, including T cells, for use in adoptive cell therapy.
Claims 35 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 in view of US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as applied to claim 25 above, and in further view of US 2016/0215261 A1 (Zonghai, L., et al) 28 July 2016.
The combination of US’533 and US’842 teach the orthogonal mammalian CAR-T cell of claim 25 as discussed in detail above.
US’533 further teaches that, to direct transmembrane polypeptides into the secretory pathway of the host cell, a secretory signal sequence (also known as a leader sequence) is provided in a polynucleotide sequence or vector sequence. The signal sequence is operably linked to the transmembrane nucleic acid and directs the synthesized polypeptide to the secretory pathway of the host cell (page 69, [0319]).
The combination of US’533 and US’842; however, do not disclose that the CAR selectively binds GPC3 or comprises one of the instantly claimed sequences.
US’261 teaches a nucleic acid encoding a CAR expressed at the surface of a T lymphocyte, said CAR comprising, connected in the order of, an extracellular binding domain, a transmembrane region, and an intracellular signaling domain, wherein the extracellular binding domain comprises a GPC3 scFv that specifically recognizes the C-terminal epitope of GPC3. US’261 further teaches genetically modified T cells expressing the CAR (abstract). US’261 teaches that GPC3 expression is reactivated in hepatocellular carcinoma and has a close association with the development of liver cancer with expression that is relatively high during early stages and increases along with the development of liver cancer. GPC3 is also expressed in tumors such as melanoma, ovarian clear cell carcinoma, yok sac tumor, neuroblastoma, and other tumors making it a candidate target for tumor immunotherapy (page 1, [0004]).
US’261 teaches a GPC3 targeting CAR comprising SEQ ID NO: 23 (page 6, [0071]), which is identical to instant SEQ ID NO: 46, as shown in the alignment below:
PNG
media_image14.png
742
631
media_image14.png
Greyscale
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of US’533 and US’842 by substituting the CAR with the GPC3 targeting CAR disclosed by US’261. It would have been obvious to make this substitution as US’261 demonstrates that the GPC3 targeting CAR had been studied in the art for expression in T cells for applications in treating cancer. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533, US’261 is teaching methods of treating cancer using CAR T cells.
Claims 36 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 in view of US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as applied to claim 25 above, and in further view of CN 108728460 A (Liu Yarong and Jin Tao) 02 Nov 2018 English Translation from Espacenet on 02/24/2026 and Douillard, P., et al (2019) Optimization of an antibody light chain framework enhances expression, biophysical properties and pharmacokinetics Antibodies 8(46); 1-16.
The combination of US’533 and US’842 teach the orthogonal mammalian CAR T cell of claim 25 as discussed in detail above.
US’533 further teaches that, to direct transmembrane polypeptides into the secretory pathway of the host cell, a secretory signal sequence (also known as a leader sequence) is provided in a polynucleotide sequence or vector sequence. The signal sequence is operably linked to the transmembrane nucleic acid and directs the synthesized polypeptide to the secretory pathway of the host cell (page 69, [0319]).
The combination of US’533 and US’842; however, does not disclose that the CAR specifically binds to GD2 and comprises the sequence recited in claim 41.
CN’460 teaches chimeric antigen receptors that target GD2 and applications thereof. Specifically, the CAR comprises an anti-GD2 single chain antibody, a human CD8 alpha hinge and transmembrane domain, a 4-1BB costimulatory region and a CD3 zeta intracellular signaling domain (pages 4-5, [0015]). CN’460 further teaches that the CAR polypeptide comprises a signal peptide (page 5, [0016]). CN’460 teaches that, preferably, the anti-GD2 monoclonal antibody is 14G2A, and teaches a CAR of SEQ ID NO: 2, which comprises an scFv that has the following alignment with instant SEQ ID NO: 49:
PNG
media_image15.png
491
622
media_image15.png
Greyscale
As shown in the alignment above, the antigen binding domain in the CAR disclosed by CN’460 differs from the instantly claimed binding domain in the linker used to join the light and heavy chain variable regions, which, in the instant sequence is (G4S)4. Additionally, the light chain variable region disclosed by CN’460 comprises a c-terminal lysine (K).
CN’460 further teaches that the light chain variable region and heavy chain variable regions are linked together by an adapter sequence and that the adapter sequence comprises a joint containing one or more repeating motifs. CN’460 teaches that the joint sequences contain G and S. For example, the motif can be GS, GGGGS, SSSSG, GSGSA, or GGSGG. The joint sequence can also include 1, 2, 3, 4, or 5 repetition motif forms (page 8, [0039]).
CN’460 further teaches the treatment of GD2 mediated diseases using CAR T cells expressing the GD2 targeting CAR, including cancers (page 13, [0061]; page 4, [0011]).
Douillard studied antibody variants in which a C-terminal lysine was omitted from the parent antibody variable region and compared to an antibody comprising the C-terminal lysine. Douillard teaches that the C-terminal lysine was omitted since it is frequently clipped during the production of antibodies (page 6, paragraph 1 and Table 1, ID 1 and 2). Table 2 demonstrates that antibodies of ID 1 and 2, which comprise an omitted lysine and an included lysine, respectively, had similar ka, kd, and KD, demonstrating similar properties with or without the C-terminal lysine.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of US’533 and US’842 by substituting the CAR with a GD2 targeting CAR comprising the antigen binding domain disclosed by CN’460. It would have further been obvious to substitute the linker in the antigen binding fragment with the (G4S)4 linker as disclosed by CN’460 and to have omitted the C-terminal lysine of the light chain variable region based on the teachings of Douillard. It would have been obvious substitute the CAR with a GD2 targeting CAR as CN’460 demonstrates that GD2 targeting CARs had been studied in the art for expression in T cells for applications in treating cancer. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533, CN’460 is teaching methods of treating cancer using CAR T cells. It would have been obvious to substitute the linker in the scFV disclosed by CN’460 with the alternative (G4S)4 linker and an ordinarily skilled artisan would have had a reasonable expectation of success because CN’460 teaches the (G4S)4 linker as an alternative for joining light and heavy chain variable regions. It would have further been obvious to omit the C-terminal lysine as Douillard teaches that this lysine is frequently clipped during the production of antibodies and demonstrates that an antibody with or without a C-terminal lysine provided similar results. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claims 51-53 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 in view of US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as applied to claims 25 and 48-50 above, and in further view of EP 0 229 108 (Katre, N. and M.J. Knauf) 27 Dec 1990 and AU 2007319657 B9 (Defrees, S. and X. Zeng) 22 May 2008.
The combination of US’533 and US’842 teach the method of claim 50 as discussed above.
As discussed above, US’842 teaches that the orthogonal IL-2 can be fused to the Fc domain of IgG, albumin, or other molecules to extend its half-life, e.g., by pegylation, glycosylation, and the like as is known in the art (page 5, [0049]).
The combination of US’533 and US’842; however, do not disclose that the PEGylated hoIL2 has the recited structures.
EP’108 teaches that many heterologous proteins, including IL-2, are found as insoluble material in refractile bodies. The problems with immunogenicity and short half-life in circulation and other undesirable properties of certain proteins are well recognized and various modifications of polypeptides have been undertaken to solve them. This includes modification of the proteins with substantially straight chain polymers, such as PEG (page 2, lines 1-36).
EP’108 teaches compounds comprising IL-2 covalently conjugated to a water soluble polymer including PEG. EP’108 further teaches that the PEG is conjugated indirectly to the protein via a grouping comprising a carboxylic acid ester, a carboxylic acid, or an amide linkage (page 4, lines 3-15). EP’108 provides the example: PEG-Carboxylic acid ester-IL-2 (page 4, line 13). As the carboxylic acid ester is used to indirectly link the PEG and IL-2, the carboxylic acid ester meets the limitation of a linker.
EP’108 teaches that the IL-2 can be a recombinant or mutein IL-2. EP’108 further teaches examples IL-2 mutants which differ from native IL-2 including des-ala1 IL-2; where “des-ala1” indicates that the N-terminal alanyl residue of IL-2 has been deleted (page 5, lines 32-38). EP’108 further teaches that the proteins are covalently bonded to the polymer including with the N-terminal amino acid group (page 6, lines 34-39).
The polymer need not have any particular molecular weight, but it is preferred that the molecular weight be between 300 and 100,000, more preferably between 350 and 40,000 (page 6, lines 58-60).
EP’108 further teaches that the IL-2 may be administered in an adoptive immunotherapy method together with isolated, lymphokine-activated lymphocytes, wherein the lymphocytes are reactive to tumor when administered with the IL-2 to humans suffering from the tumor (page 7, lines 60-64).
AU’657 teaches glycopegylated molecules produced by enzyme mediated formation of a conjugate between glycosylated or nonglycosylated peptides and an enzymatically transferable saccharide moiety that includes a modifying group, such as PEG within its structure. AU’657 teaches that exemplary peptides include IL-2 (page 1, [0002]). AU’657 teaches that the PEG can be linear or branched (pages 16-17, [0055]-[0056]). Although the molecular weight of the polymer can vary, it is typically in the range from about 100 to about 100 Da, often from about 6,000 Da to 80,000 Da (page 17, [0057]). AU’657 also teaches that the PEG has a molecular weight from about 20 kD to about 60kD, from about 30kD to about 50kD, and even more preferably 40kD (page 33, [0115]).
AU’657 teaches that the conjugates increase therapeutic half-life due to, for example, reduced clearance rate or reduced rate of uptake by the immune or reticuloendothelial system (RES) (pages 28-29, [0101]).
AU’657 teaches that the conjugates typically correspond to the structure:
PNG
media_image16.png
102
444
media_image16.png
Greyscale
Where the agent is PEG and the linker is any of a wide array of linking groups. Alternatively, the linker may be a single bond or a “zero order linker” (page 30, [0107]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of US’533 and US’842 with the teachings of EP’108 and AU’657 to arrive at the instantly claimed pegylated hoIL2 structures. Specifically, it would have been obvious to use a PEG-linker-hoIL2 format as taught by EP’108 and AU’657 to form the pegylated IL-2 taught by the combination of US’533 and US’842. It would have been obvious to use the methods taught by EP’108 and AU’657 for conjugating the IL-2 to PEG as the references demonstrate methods known and practiced in the art for the conjugation of peptides, including IL-2, to PEG for purposes of increasing half-life during therapeutic use. An ordinarily skilled artisan would have had a reasonable expectation of success as US’842 teaches that the orthogonal IL-2 disclosed can be pegylated and both EP’108 and AU’657 both teach embodiments where the peptide conjugated to PEG is IL-2.
Regarding the structure of the hIL2 recited in instant claims 52 and 53, US’842 teaches that human IL-2 has a structure of SEQ ID NO: 4 as discussed in detail above. This sequence differs from instant SEQ ID NO: 23 by des-ala1, E15S, H16Q, L19V, D20L, Q22K and M23A, as shown in the alignment below:
PNG
media_image17.png
230
586
media_image17.png
Greyscale
As discussed above, US’842 teaches an orthogonal IL-2 of SQVLKA, with E15S, H16Q, L19V, D20L, Q22K, and M23A (page 17 Table 1). Additionally, as discussed above, EP’108 teaches modified IL-2 conjugated to PEG including des-Ala1.
These modifications, combined, result in an amino acid sequence that is identical to instant SEQ ID NO: 23.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the SQVLKA orthogonal IL-2 disclosed by US’842 in the pegylated IL-2 to further comprise a des-Ala1 mutation taught by EP’108. It would have been obvious to make this additional modification as EP’108 teaches that such modification was known in the art and teaches the modification in pegylated IL-2.
Claim 54 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 in view of US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 and WO 2017/028374 A1 (Yonghao, Y., et al) 23 Feb 2017.
The teachings of US’533 are as discussed in detail above.
US’533 further teaches methods of engineering the immune cell comprising a cell expressing an inducible chimeric cytokine receptor and at least one CAR at the surface of the cell (page 69, [0320]).
US’533; however, does not disclose that the inducible cytokine receptor is an orthogonal hCD122 receptor of SEQ ID NO: 29 or that the CD19 CAR has a sequence of SEQ ID NO: 30 as claimed.
The teachings of US’842 and WO’374 are as discussed in detail above.
As discussed above, US’842 teaches that the orthogonal human IL-2RB receptor has a sequence of SEQ ID NO: 9. US’842, SEQ ID NO: 9 is identical to instant SEQ ID NO: 29 as shown in the alignment below:
PNG
media_image18.png
592
577
media_image18.png
Greyscale
As discussed above, WO’374 teaches a CD19 CAR that comprises an amino acid sequence that is identical to instant SEQ ID NO: 30.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the T cells of US’533 by substituting the inducible chimeric cytokine receptor disclosed by US’533 with the orthogonal IL-2RB (CD122) receptor disclosed by US’842 and by using the CD19 CAR sequence disclosed by WO’374 as the CAR in the cell. It would have been obvious to substitute the inducible chimeric cytokine receptors of US’533 with the orthogonal IL-2RB receptor as both US’533 and US’842 are teaching inducible cytokine receptors for use in immune cells, such as T cells, for use in adoptive cell therapy in which the cytokine receptor is activated by the administration of an exogenous peptide, such as a ligand. An ordinarily skilled artisan would have further had a reasonable expectation of success because US’533 teaches that the inducible chimeric cytokine receptors disclosed can comprise a signaling domain from a cytokine, including IL2Rb, suggesting the use of the same signaling. An ordinarily skilled artisan would have been able to use the CD19 CAR disclosed by WO’374 with a reasonable expectation of success because both CARs target the same antigen, CD19, and are taught for expression in immune cells, including T cells, for use in adoptive cell therapy. Furthermore, US’533 teaches that the CAR can comprise a signal peptide, a CD19 scFv, a transmembrane domain, co-stimulatory domain from CD28 and an intracellular signaling domain from TCRζ (which is the ζ chain of CD3), demonstrating the same types of domains as those presented in the CD19 CAR of WO’374.
Claim 55 is rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 in view of US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 and US 2016/0215261 A1 (Zonghai, L., et al) 28 July 2016.
The teachings of US’533 are as discussed in detail above.
US’533; however, does not disclose that the inducible cytokine receptor is an orthogonal hCD122 receptor of SEQ ID NO: 29 or that the CAR selectively binds GPC3 and has a sequence of instant SEQ ID NO: 45 or 46.
The teachings of US’842 and US’261 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the T cells of US’533 by substituting the inducible chimeric cytokine receptor disclosed by US’533 with the orthogonal IL-2RB (CD122) receptor disclosed by US’842 and by substituting the CAR with the GPC3 targeting CAR disclosed by US’261. It would have been obvious to substitute the inducible chimeric cytokine receptors of US’533 with the orthogonal IL-2RB receptor as both US’533 and US’842 are teaching inducible cytokine receptors for use in immune cells, such as T cells, for use in adoptive cell therapy in which the cytokine receptor is activated by the administration of an exogenous peptide, such as a ligand. An ordinarily skilled artisan would have further had a reasonable expectation of success because US’533 teaches that the inducible chimeric cytokine receptors disclosed can comprise a signaling domain from a cytokine, including IL2Rb, suggesting the use of the same signaling. It would have been obvious to substitute the CAR with the GPC3 targeting CAR of US’261 as US’261 demonstrates that GPC3 targeting CARs had been studied in the art for expression in T cells for applications in treating cancer. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533, US’261 is teaching methods of treating cancer using CAR T cells.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 11,648,296 B2
Claims 1-14, 19-22, 25-29, 32, 34, 42-46, and 48-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 11,648,296 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018.
US’296 claims a human IL-2 (hIL2) ortholog polypeptide consisting of the amino acid sequence set forth in SEQ ID NO: 20, wherein PEG is linked to the amino terminus of the polypeptide and the PEG is a 40kD branched PEG comprising two 20 kD arms. US’296 further claims a pharmaceutical composition comprising the hIL2 ortholog polypeptide.
US’296, SEQ ID NO: 20, is identical to instant SEQ ID NO: 23 as recited in instant claim 53, as shown in the alignment below:
PNG
media_image19.png
228
585
media_image19.png
Greyscale
The claims of US’296 differ from the instant claims in that the instant claims are drawn to methods of treating a disease, disorder, or condition comprising the recited method steps, which include administration of an orthogonal ligand to a subject with cells expressing an orthogonal hCD122. The instant claims also include orthogonal mammalian CAR T cells.
The teachings of US’533 and US’842 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’296 by using the human IL-2 ortholog polypeptide and pharmaceutical composition thereof in a method of treating disease, disorder, or condition as instantly claimed based on the teachings of US’533 and US’842. It would have been obvious to make this combination as US’296 claims an orthogonal IL-2 and US’533 and US’842 teaches methods of treating in which T cells, or CAR T cells, are modified to express an orthogonal CD122 receptor which are then administered in combination with an orthogonal IL-2 polypeptide. Additionally, US’842 teaches that the IL-2 can be pegylated to extend half-life demonstrating that the use of such an IL-2 ortholog had been considered in the art.
Claims 15-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 11,648,296 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of EP 3 126 380 B1 (Pule, M., et al) 08 Feb 2017.
The claims of US’296 modified by US’533 and US’842 teach the method of instant claim 1 as discussed above.
The combination of applied references, however, do not disclose the recited regimens for the administration of the orthogonal ligand.
The teachings of EP’380 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of US’296, US’533 and US’842 by monitoring the progression of the disease and/or toxic activity and adjusting the dose of the orthogonal ligand in order to achieve acceptable levels of disease progression and/or toxicity as taught by EP’380 to arrive at the instant claims. An ordinarily skilled artisan would have been motivated to adjust the administration of the orthogonal ligand in order to optimize treatment based on progression of the disease and/or toxicity. An ordinarily skilled artisan would have had a reasonable expectation of success as, like US’533 and US’842, EP’380 teaches methods of using CAR T cells to treat diseases such as cancer using inducible elements that allow for the control of cell activation and proliferation. Additionally, EP’380 demonstrates that modulation by increasing administration or stopping administration of an inducing element had been considered in the art. Specifically, EP’380 teaches that administering the ligand induces activation/proliferation of the cells and stopping administration of the ligand reduces or stops activation/proliferation of the cells.
Furthermore, the determination of the optimal timing or amounts is considered to be routine optimization when the art had considered the impacts of such elements. See MPEP 2144.05 (II) A. In this case, US’842 teaches that the cells are administered at dosages which include 105 and 106 engineered cells/kg and teaches that the engineered cells increase the cytolytic response of the T cells towards elimination of tumor cells (page 11, [0111]); US’533 demonstrates administration of an inducing ligand to a chimeric cytokine receptor periodically over more than two weeks; and EP’380 demonstrates monitoring and adjusting ligand dosage as a means to modulate the activation/proliferation of inducible CAR T cells in an effort to optimize disease treatment. It would have been obvious to use these teachings and optimization that was known and practiced in the art in order to arrive at the instantly claimed invention.
Claims 30-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 11,648,296 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of US 2018/0037630 A1 (Tanaka, S., et al) 8 Feb 2018.
The claims of US’296 modified by US’533 and US’842 teach the CAR T cell of instant claim 29 as discussed above.
The combination of applied references, however, do not disclose that the intracellular domain of the receptor further comprises at least one STAT3 signaling motif as recited in claims 30-31.
The teachings of US’630 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR T cell taught by the combination of US’296, US’533 and US’842 by further including at least one STAT3 motif as taught by US’630. An ordinarily skilled artisan would have been motivated to further include a STAT3 motif as US’630 demonstrates that signaling domains that further comprise the STAT3 signaling motifs provide superior proliferation though higher cell division and reduced apoptosis as well as decreased tumor activity and increases in overall survival. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533 and US’842, US’630 is teaching the treatment of diseases, such as cancer, using CAR T cells. Additionally, US’630 teaches the use of the cytoplasmic domain of IL2RB, which is the same domain taught by US’842.
Claims 37 and 54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 11,648,296 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of WO 2017/028374 A1 (Yonghao, Y., et al) 23 Feb 2017.
The claims of US’296 modified by US’533 and US’842 teach the CAR T cell of instant claim 32 as discussed above.
The combination of applied references; however, do not disclose that the CAR that binds to CD19 comprises one of the sequences recited in instant claim 37.
The teachings of WO’374 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of US’296, US’533 and US’842 by using the CD19 targeting CAR sequence disclosed by WO’374 as the CAR that targets CD19. An ordinarily skilled artisan would have been able to make this substitution with a reasonable expectation of success because both CARs target the same antigen, CD19, and are taught for expression in immune cells, including T cells, for use in adoptive cell therapy. Furthermore, US’533 teaches that the CAR can comprise a signal peptide, a CD19 scFv, a transmembrane domain, co-stimulatory domain from CD28 and an intracellular signaling domain from TCRζ (which is the ζ chain of CD3), demonstrating the same types of domains as those presented in the CD19 CAR of WO’374.
Claims 33 and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 11,648,296 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of US 2018/0022815 A1 (Chang, L.) 25 Jan 2018, WO 2018/161017 (Suri, V., et al) 07 Sept 2018 and US 2018/0265585 A1 (Seogkyoung, K.) 20 Sept 2018.
The claims of US’296 modified by US’533 and US’842 teach the CAR T cell of instant claim 25 as discussed above.
The combination of applied references; however, do not disclose that the CAR that binds to PSMA or comprises one of the sequences recited in instant claim 38.
The teachings of US’815, WO’017, and US’585 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of US’296, US’533 and US’842 by substituting the CAR with a PSMA targeting CAR comprising the signal peptide and heavy and light chain variable regions disclosed by US’380. It would have further been obvious to substitute the linker in the PSMA CAR with the alternative linker disclosed by US’815, to use the CD8a hinge, transmembrane domain, and 4-1BB costimulatory domain taught by WO’017, and to use the CD3z intracellular signaling domain disclosed by US’585. It would have been obvious to substitute the CAR with a CAR targeting PSMA as US’380 demonstrates that the PSMA targeting CARs had been studied in the art for expression in T cells for applications in treating cancer. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533, US’380 is teaching methods of treating cancer using CAR T cells. It would have been obvious to substitute the domains of the CAR with the alternatives disclosed by US’815, WO’017, and US’585 as the references teach alternative amino acid sequences for the same domains for use in CAR T cell production. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claim 39 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 11,648,296 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of WO 2018/140725 A1 (Posey, A.D. and S. Guedan Carrio) 02 Aug 2018.
The claims of US’296 modified by US’533 and US’842 teach the CAR T cell of instant claim 34 as discussed above.
The combination of applied references; however, do not disclose that the CAR that binds to BCMA comprises one of the sequences recited in instant claim 39.
The teachings of WO’725 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of US’296, US’533 and US’842 by using the BCMA targeting CAR sequence disclosed by WO’725 as the CAR that targets BCMA. An ordinarily skilled artisan would have been able to make this substitution with a reasonable expectation of success because both CARs target the same antigen, BCMA, and are taught for expression in immune cells, including T cells, for use in adoptive cell therapy.
Claims 35, 40, and 55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 11,648,296 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of US 2016/0215261 A1 (Zonghai, L., et al) 28 July 2016.
The claims of US’296 modified by US’533 and US’842 teach the CAR T cell of instant claim 25 as discussed above.
The combination of applied references; however, do not disclose that the CAR selectively binds GPC3 or comprises one of the instantly claimed sequences.
The teachings of US’261 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of US’296, US’533 and US’842 by substituting the CAR with the GPC3 targeting CAR disclosed by US’261. It would have been obvious to make this substitution as US’261 demonstrates that the GPC3 targeting CAR had been studied in the art for expression in T cells for applications in treating cancer. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533, US’261 is teaching methods of treating cancer using CAR T cells.
Claims 36 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 11,648,296 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of CN 108728460 A (Liu Yarong and Jin Tao) 02 Nov 2018 English Translation from Espacenet on 02/24/2026 and Douillard, P., et al (2019) Optimization of an antibody light chain framework enhances expression, biophysical properties and pharmacokinetics Antibodies 8(46); 1-16.
The claims of US’296 modified by US’533 and US’842 teach the CAR T cell of instant claim 25 as discussed above.
The combination of applied references; however, does not disclose that the CAR specifically binds to GD2 and comprises the sequence recited in claim 41.
The teachings of CN’460 and Douillard are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of US’296, US’533 and US’842 by substituting the CAR with a GD2 targeting CAR comprising the antigen binding domain disclosed by CN’460. It would have further been obvious to substitute the linker in the antigen binding fragment with the (G4S)4 linker as disclosed by CN’460 and to have omitted the C-terminal lysine of the light chain variable region based on the teachings of Douillard. It would have been obvious substitute the CAR with a GD2 targeting CAR as CN’460 demonstrates that GD2 targeting CARs had been studied in the art for expression in T cells for applications in treating cancer. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533, CN’460 is teaching methods of treating cancer using CAR T cells. It would have been obvious to substitute the linker in the scFV disclosed by CN’460 with the alternative (G4S)4 linker and an ordinarily skilled artisan would have had a reasonable expectation of success because CN’460 teaches the (G4S)4 linker as an alternative for joining light and heavy chain variable regions. It would have further been obvious to omit the C-terminal lysine as Douillard teaches that this lysine is frequently clipped during the production of antibodies and demonstrates that an antibody with or without a C-terminal lysine provided similar results. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
17/783,505
Claims 1-14, 19-22, 25-29, 30-32, 34, 42-46, and 48-50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 15-18, and 28-30 of copending Application No. 17/783,505 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018.
App’505 claims a polynucleotide encoding a modified human CD122, wherein the modified human CD122 comprises one or more STAT3 binding motifs. App’505 further claims that the CD122 is an orthogonal CD122 that is modified at one or more residues including R41, R42, Q70, K71, T73, T74, V75, S132, H133, Y134, F135, E136, and Q214 relative to native human CD122. App’505 further claims that the CD122 is linked to two or three STAT3 binding motifs, that the STAT3 binding motifs comprise a sequence of YX1X2Q, where X1 is selected from the group consisting of L, R, F, M and X2 is selected from the group consisting of R, K, H, P, including motifs of YLRQ, YLKQ, YRHQ, YLRQ, YFKQ, YLPQ, YMPQ, and YDKPH. App’505 further claims an expression vector comprising the polynucleotide, and a cell comprising the polynucleotide expressing the modified human CD122. US’505 further claims that the cell is a human immune cell and further expresses a CAR, including a CD19 and a BCMA CAR. App’505 claims a method of stimulating an immune cell expressing a modified human CD122 comprising one or more STAT3 binding motifs, the method comprising contacting the immune cell with a human IL2 polypeptide where the stimulating occurs ex vivo or in vivo.
The claims of App’505 differ from the instantly claimed invention in that the instantly claimed invention is drawn to methods of treating a disease, disorder, or condition and further limits the human CD122 and CARs that are expressed in the immune cells.
The teachings of US’533 and US’842 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’505 by using the immune cells expressing the CAR and the modified CD122 receptor in a method of treating disease, disorder, or condition as instantly claimed based on the teachings of US’533 and US’842. It would have been obvious to make this combination as App’505 teaches modified CD122 receptors, including orthogonal CD122, expressed in an immune cell with a CAR and the combination of US’533 and US’842 teach the use of such cells in the treatment of diseases, disorders, or conditions.
Claims 15-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 15-18, and 28-30 of copending Application No. 17/783,505 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of EP 3 126 380 B1 (Pule, M., et al) 08 Feb 2017.
The claims of App’505 modified by US’533 and US’842 teach the method of instant claim 1 as discussed above.
The combination of applied references, however, do not disclose the recited regimens for the administration of the orthogonal ligand.
The teachings of EP’380 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of App’505, US’533 and US’842 by monitoring the progression of the disease and/or toxic activity and adjusting the dose of the orthogonal ligand in order to achieve acceptable levels of disease progression and/or toxicity as taught by EP’380 to arrive at the instant claims. An ordinarily skilled artisan would have been motivated to adjust the administration of the orthogonal ligand in order to optimize treatment based on progression of the disease and/or toxicity. An ordinarily skilled artisan would have had a reasonable expectation of success as, like US’533 and US’842, EP’380 teaches methods of using CAR T cells to treat diseases such as cancer using inducible elements that allow for the control of cell activation and proliferation. Additionally, EP’380 demonstrates that modulation by increasing administration or stopping administration of an inducing element had been considered in the art. Specifically, EP’380 teaches that administering the ligand induces activation/proliferation of the cells and stopping administration of the ligand reduces or stops activation/proliferation of the cells.
Furthermore, the determination of the optimal timing or amounts is considered to be routine optimization when the art had considered the impacts of such elements. See MPEP 2144.05 (II) A. In this case, US’842 teaches that the cells are administered at dosages which include 105 and 106 engineered cells/kg and teaches that the engineered cells increase the cytolytic response of the T cells towards elimination of tumor cells (page 11, [0111]); US’533 demonstrates administration of an inducing ligand to a chimeric cytokine receptor periodically over more than two weeks; and EP’380 demonstrates monitoring and adjusting ligand dosage as a means to modulate the activation/proliferation of inducible CAR T cells in an effort to optimize disease treatment. It would have been obvious to use these teachings and optimization that was known and practiced in the art in order to arrive at the instantly claimed invention.
Claims 37 and 54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 15-18, and 28-30 of copending Application No. 17/783,505 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of WO 2017/028374 A1 (Yonghao, Y., et al) 23 Feb 2017.
The claims of App’505 modified by US’533 and US’842 teach the CAR T cell of instant claim 32 as discussed above.
The combination of applied references; however, do not disclose that the CAR that binds to CD19 comprises one of the sequences recited in instant claim 37.
The teachings of WO’374 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of App’505, US’533 and US’842 by using the CD19 targeting CAR sequence disclosed by WO’374 as the CAR that targets CD19. An ordinarily skilled artisan would have been able to make this substitution with a reasonable expectation of success because both CARs target the same antigen, CD19, and are taught for expression in immune cells, including T cells, for use in adoptive cell therapy. Furthermore, US’533 teaches that the CAR can comprise a signal peptide, a CD19 scFv, a transmembrane domain, co-stimulatory domain from CD28 and an intracellular signaling domain from TCRζ (which is the ζ chain of CD3), demonstrating the same types of domains as those presented in the CD19 CAR of WO’374.
Claims 33 and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 15-18, and 28-30 of copending Application No. 17/783,505 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of US 2018/0022815 A1 (Chang, L.) 25 Jan 2018, WO 2018/161017 (Suri, V., et al) 07 Sept 2018 and US 2018/0265585 A1 (Seogkyoung, K.) 20 Sept 2018.
The claims of App’505 modified by US’533 and US’842 teach the CAR T cell of instant claim 25 as discussed above.
The combination of applied references; however, do not disclose that the CAR that binds to PSMA or comprises one of the sequences recited in instant claim 38.
The teachings of US’815, WO’017, and US’585 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of App’505, US’533 and US’842 by substituting the CAR with a PSMA targeting CAR comprising the signal peptide and heavy and light chain variable regions disclosed by US’380. It would have further been obvious to substitute the linker in the PSMA CAR with the alternative linker disclosed by US’815, to use the CD8a hinge, transmembrane domain, and 4-1BB costimulatory domain taught by WO’017, and to use the CD3z intracellular signaling domain disclosed by US’585. It would have been obvious to substitute the CAR with a CAR targeting PSMA as US’380 demonstrates that the PSMA targeting CARs had been studied in the art for expression in T cells for applications in treating cancer. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533, US’380 is teaching methods of treating cancer using CAR T cells. It would have been obvious to substitute the domains of the CAR with the alternatives disclosed by US’815, WO’017, and US’585 as the references teach alternative amino acid sequences for the same domains for use in CAR T cell production. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claim 39 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 15-18, and 28-30 of copending Application No. 17/783,505 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of WO 2018/140725 A1 (Posey, A.D. and S. Guedan Carrio) 02 Aug 2018.
The claims of App’505 modified by US’533 and US’842 teach the CAR T cell of instant claim 34 as discussed above.
The combination of applied references; however, do not disclose that the CAR that binds to BCMA comprises one of the sequences recited in instant claim 39.
The teachings of WO’725 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of App’505, US’533 and US’842 by using the BCMA targeting CAR sequence disclosed by WO’725 as the CAR that targets BCMA. An ordinarily skilled artisan would have been able to make this substitution with a reasonable expectation of success because both CARs target the same antigen, BCMA, and are taught for expression in immune cells, including T cells, for use in adoptive cell therapy.
Claims 35, 40, and 55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 15-18, and 28-30 of copending Application No. 17/783,505 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of US 2016/0215261 A1 (Zonghai, L., et al) 28 July 2016.
The claims of App’505 modified by US’533 and US’842 teach the CAR T cell of instant claim 25 as discussed above.
The combination of applied references; however, do not disclose that the CAR selectively binds GPC3 or comprises one of the instantly claimed sequences.
The teachings of US’261 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of App’505, US’533 and US’842 by substituting the CAR with the GPC3 targeting CAR disclosed by US’261. It would have been obvious to make this substitution as US’261 demonstrates that the GPC3 targeting CAR had been studied in the art for expression in T cells for applications in treating cancer. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533, US’261 is teaching methods of treating cancer using CAR T cells.
Claims 36 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 15-18, and 28-30 of copending Application No. 17/783,505 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of CN 108728460 A (Liu Yarong and Jin Tao) 02 Nov 2018 English Translation from Espacenet on 02/24/2026 and Douillard, P., et al (2019) Optimization of an antibody light chain framework enhances expression, biophysical properties and pharmacokinetics Antibodies 8(46); 1-16.
The claims of App’505 modified by US’533 and US’842 teach the CAR T cell of instant claim 25 as discussed above.
The combination of applied references; however, does not disclose that the CAR specifically binds to GD2 and comprises the sequence recited in claim 41.
The teachings of CN’460 and Douillard are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of App’505, US’533 and US’842 by substituting the CAR with a GD2 targeting CAR comprising the antigen binding domain disclosed by CN’460. It would have further been obvious to substitute the linker in the antigen binding fragment with the (G4S)4 linker as disclosed by CN’460 and to have omitted the C-terminal lysine of the light chain variable region based on the teachings of Douillard. It would have been obvious substitute the CAR with a GD2 targeting CAR as CN’460 demonstrates that GD2 targeting CARs had been studied in the art for expression in T cells for applications in treating cancer. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533, CN’460 is teaching methods of treating cancer using CAR T cells. It would have been obvious to substitute the linker in the scFV disclosed by CN’460 with the alternative (G4S)4 linker and an ordinarily skilled artisan would have had a reasonable expectation of success because CN’460 teaches the (G4S)4 linker as an alternative for joining light and heavy chain variable regions. It would have further been obvious to omit the C-terminal lysine as Douillard teaches that this lysine is frequently clipped during the production of antibodies and demonstrates that an antibody with or without a C-terminal lysine provided similar results. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
18/843,379
Claims 1-14, 19-22, 25-29, 32, 34-35, 42-46, and 48-53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/843,379 in view of 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018.
App’379 claims a GPC3 CAR comprising an antigen binding domain that binds to GPC3 comprising an scFv of SEQ ID NO: 10. App’379 further claims the CAR comprises a CD3 zeta signaling domain and a costimulatory domain selected from CD28 and 41BB. The claims further recite that the CAR is selected from the group consisting of SEQ ID NO: 34-40. App’379 claims a nucleic acid encoding the GPC3 CAR, and a recombinant expression vector comprising the nucleic acid, including a lentiviral or retroviral vector.
App’379 further claims that the vector further comprises a nucleic acid sequence encoding an ortho CD122 receptor, where the two are operably linked to at least one expression control sequence functional in a mammalian T cell. App’379 further claims that the nucleic acid sequences encoding the GPC3 CAR and ortho CD122 are operably linked to a single control sequence and are separated by an IRES or T2A sequence. App’379 claims a recombinantly modified T cell comprising the recombinant vector. App’379 claims an ortho GPC3 CAR T cell, the cell expressing an ortho CD122 and a GPC3 CAR, wherein the ortho CD122 comprises amino acid substitutions in positions 133 and/or 134, numbered in accordance with wild-type hCDR122. The GPC3 CAR is claimed as comprising the sequence of SEQ ID NO: 37 and the ortho CD122 having the amino acid sequence of SEQ ID NO: 4.
App’379 further claims a method of making an ortho GPC3 CAR T cell, the method comprising: obtaining a sample of PBMCs, contacting the PBMCs with beads coted with CD3 and CD28 to provide a population of activated PBMCS, isolating CD8+ and CD4+ T cells, contacting the isolated population of cells with a recombinant lentiviral vector comprising an expression cassette comprising from the 5’ to 3’: a promoter active in T cells, a nucleic acid encoding a signal peptide, a nucleic acid encoding a GPC3 CAR, a T2A sequence, a nucleic acid sequence encoding a signal peptide, a nucleic acid sequence encoding the ortho CD122 of SEQ ID NO: 4 such that a fraction of the population of T cells is transduced with the lentiviral vector, and contacting the population of cells with ortho IL2, selected from the group consisting of human mutein containing the amino acid substitutions E15S/H16Q/L119V/D20L/Q22K/M23A; an ortho IL2 of SEQ ID NO: 9 (STK-007) or a pegylated version thereof (STK-009).
App’379 further claims an ortho GPC3 CAR T cell prepared in accordance with the claimed method as well as a method of treating or preventing a neoplastic disease, disorder, or condition, comprising administering to the subject a therapeutically effective amount of the ortho GPC3 CAR T in combination with an effective dose of ortho IL.
App’379 further claims that the ortho IL-2 used ex vivo is different than the orthogonal ligand used in vivo and that the subject is treated with a lymphodepleting regimen prior to administration of the CAR T cells.
App’379 teaches a method of generating an ortho GPC3 CAR T cell product substantially enriched for a population of ortho GPC3 CAR T cells, the method comprising the steps of:
Isolating a population of cells from a mammalian subject, the population of cells comprising T cells; contacting the isolated population of cells with a recombinant vector comprising a first nucleic acid sequence encoding a GP3 CAR and a second nucleic acid encoding an ortho CD122, the first and second nucleic acids operably linked to an expression control sequence operable in a mammalian T cell and separated by an IRES or T2A sequence such that the cell expresses the CAR and the ortho CD122; and contacting the isolated population of cells ex vivo with a quantity of ortho IL2 sufficient to induce proliferation of cells transduced by the contacting in step (b); wherein the contacting with the ortho IL2 is maintained for a period of time such that the fraction of cells expressing the CAR and C122 comprise at least 10% of the population.
The claims of App’379 differ from the instantly claimed methods and cells in that the instantly claimed methods recite that the fraction of cells expressing the CAR and C122 comprise at least 20% of the population.
The teachings of US’533 and US’842 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’379 with the teachings of US’533 and US’842 to arrive at the instantly claimed methods. It would have been obvious to arrive at the instantly claimed methods, including a population of cells where at least 20% are transduced based on the teachings of US’533 and US’842 which demonstrate similar methods and demonstrate transduction of at least 20% of cells in a cell population.
Claims 15-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/843,379 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of EP 3 126 380 B1 (Pule, M., et al) 08 Feb 2017.
The claims of App’379 modified by US’533 and US’842 teach the method of instant claim 1 as discussed above.
The combination of applied references, however, do not disclose the recited regimens for the administration of the orthogonal ligand.
The teachings of EP’380 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of App’379, US’533 and US’842 by monitoring the progression of the disease and/or toxic activity and adjusting the dose of the orthogonal ligand in order to achieve acceptable levels of disease progression and/or toxicity as taught by EP’380 to arrive at the instant claims. An ordinarily skilled artisan would have been motivated to adjust the administration of the orthogonal ligand in order to optimize treatment based on progression of the disease and/or toxicity. An ordinarily skilled artisan would have had a reasonable expectation of success as, like US’533 and US’842, EP’380 teaches methods of using CAR T cells to treat diseases such as cancer using inducible elements that allow for the control of cell activation and proliferation. Additionally, EP’380 demonstrates that modulation by increasing administration or stopping administration of an inducing element had been considered in the art. Specifically, EP’380 teaches that administering the ligand induces activation/proliferation of the cells and stopping administration of the ligand reduces or stops activation/proliferation of the cells.
Furthermore, the determination of the optimal timing or amounts is considered to be routine optimization when the art had considered the impacts of such elements. See MPEP 2144.05 (II) A. In this case, US’842 teaches that the cells are administered at dosages which include 105 and 106 engineered cells/kg and teaches that the engineered cells increase the cytolytic response of the T cells towards elimination of tumor cells (page 11, [0111]); US’533 demonstrates administration of an inducing ligand to a chimeric cytokine receptor periodically over more than two weeks; and EP’380 demonstrates monitoring and adjusting ligand dosage as a means to modulate the activation/proliferation of inducible CAR T cells in an effort to optimize disease treatment. It would have been obvious to use these teachings and optimization that was known and practiced in the art in order to arrive at the instantly claimed invention.
Claims 30-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/843,379 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of US 2018/0037630 A1 (Tanaka, S., et al) 8 Feb 2018.
The claims of App’379 modified by US’533 and US’842 teach the CAR T cell of instant claim 29 as discussed above.
The combination of applied references, however, do not disclose that the intracellular domain of the receptor further comprises at least one STAT3 signaling motif as recited in claims 30-31.
The teachings of US’630 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR T cell taught by the combination of App’379, US’533 and US’842 by further including at least one STAT3 motif as taught by US’630. An ordinarily skilled artisan would have been motivated to further include a STAT3 motif as US’630 demonstrates that signaling domains that further comprise the STAT3 signaling motifs provide superior proliferation though higher cell division and reduced apoptosis as well as decreased tumor activity and increases in overall survival. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533 and US’842, US’630 is teaching the treatment of diseases, such as cancer, using CAR T cells. Additionally, US’630 teaches the use of the cytoplasmic domain of IL2RB, which is the same domain taught by US’842.
Claims 37 and 54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/843,379 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of WO 2017/028374 A1 (Yonghao, Y., et al) 23 Feb 2017.
The claims of App’379 modified by US’533 and US’842 teach the CAR T cell of instant claim 32 as discussed above.
The combination of applied references; however, do not disclose that the CAR that binds to CD19 comprises one of the sequences recited in instant claim 37.
The teachings of WO’374 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of App’379, US’533 and US’842 by using the CD19 targeting CAR sequence disclosed by WO’374 as the CAR that targets CD19. An ordinarily skilled artisan would have been able to make this substitution with a reasonable expectation of success because both CARs target the same antigen, CD19, and are taught for expression in immune cells, including T cells, for use in adoptive cell therapy. Furthermore, US’533 teaches that the CAR can comprise a signal peptide, a CD19 scFv, a transmembrane domain, co-stimulatory domain from CD28 and an intracellular signaling domain from TCRζ (which is the ζ chain of CD3), demonstrating the same types of domains as those presented in the CD19 CAR of WO’374.
Claims 33 and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/843,379 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of US 2018/0022815 A1 (Chang, L.) 25 Jan 2018, WO 2018/161017 (Suri, V., et al) 07 Sept 2018 and US 2018/0265585 A1 (Seogkyoung, K.) 20 Sept 2018.
The claims of App’379 modified by US’533 and US’842 teach the CAR T cell of instant claim 25 as discussed above.
The combination of applied references; however, do not disclose that the CAR that binds to PSMA or comprises one of the sequences recited in instant claim 38.
The teachings of US’815, WO’017, and US’585 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of App’379, US’533 and US’842 by substituting the CAR with a PSMA targeting CAR comprising the signal peptide and heavy and light chain variable regions disclosed by US’380. It would have further been obvious to substitute the linker in the PSMA CAR with the alternative linker disclosed by US’815, to use the CD8a hinge, transmembrane domain, and 4-1BB costimulatory domain taught by WO’017, and to use the CD3z intracellular signaling domain disclosed by US’585. It would have been obvious to substitute the CAR with a CAR targeting PSMA as US’380 demonstrates that the PSMA targeting CARs had been studied in the art for expression in T cells for applications in treating cancer. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533, US’380 is teaching methods of treating cancer using CAR T cells. It would have been obvious to substitute the domains of the CAR with the alternatives disclosed by US’815, WO’017, and US’585 as the references teach alternative amino acid sequences for the same domains for use in CAR T cell production. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claim 39 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/843,379 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of WO 2018/140725 A1 (Posey, A.D. and S. Guedan Carrio) 02 Aug 2018.
The claims of App’379 modified by US’533 and US’842 teach the CAR T cell of instant claim 34 as discussed above.
The combination of applied references; however, do not disclose that the CAR that binds to BCMA comprises one of the sequences recited in instant claim 39.
The teachings of WO’725 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of App’379, US’533 and US’842 by using the BCMA targeting CAR sequence disclosed by WO’725 as the CAR that targets BCMA. An ordinarily skilled artisan would have been able to make this substitution with a reasonable expectation of success because both CARs target the same antigen, BCMA, and are taught for expression in immune cells, including T cells, for use in adoptive cell therapy.
Claims 40, and 55 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/843,379 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of US 2016/0215261 A1 (Zonghai, L., et al) 28 July 2016.
The claims of App’379 modified by US’533 and US’842 teach the CAR T cell of instant claim 25 as discussed above.
The combination of applied references; however, do not disclose that the CAR that selectively binds GPC3 comprises one of the instantly claimed sequences.
The teachings of US’261 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of App’379, US’533 and US’842 by substituting the CAR with the GPC3 targeting CAR disclosed by US’261. It would have been obvious to make this substitution as US’261 demonstrates that the GPC3 targeting CAR had been studied in the art for expression in T cells for applications in treating cancer. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533, US’261 is teaching methods of treating cancer using CAR T cells.
Claims 36 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/843,379 in view of US 2019/0292533 A1 (Nager, A.R., et al) 26 Sept 2019 and US 2018/0228842 A1 (Garcia, K.C., et al) 16 Aug 2018 as discussed above, and in further view of CN 108728460 A (Liu Yarong and Jin Tao) 02 Nov 2018 English Translation from Espacenet on 02/24/2026 and Douillard, P., et al (2019) Optimization of an antibody light chain framework enhances expression, biophysical properties and pharmacokinetics Antibodies 8(46); 1-16.
The claims of App’379 modified by US’533 and US’842 teach the CAR T cell of instant claim 25 as discussed above.
The combination of applied references; however, does not disclose that the CAR specifically binds to GD2 and comprises the sequence recited in claim 41.
The teachings of CN’460 and Douillard are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the orthogonal mammalian CAR-T cell taught by the combination of App’379, US’533 and US’842 by substituting the CAR with a GD2 targeting CAR comprising the antigen binding domain disclosed by CN’460. It would have further been obvious to substitute the linker in the antigen binding fragment with the (G4S)4 linker as disclosed by CN’460 and to have omitted the C-terminal lysine of the light chain variable region based on the teachings of Douillard. It would have been obvious substitute the CAR with a GD2 targeting CAR as CN’460 demonstrates that GD2 targeting CARs had been studied in the art for expression in T cells for applications in treating cancer. An ordinarily skilled artisan would have had a reasonable expectation of success because, like US’533, CN’460 is teaching methods of treating cancer using CAR T cells. It would have been obvious to substitute the linker in the scFV disclosed by CN’460 with the alternative (G4S)4 linker and an ordinarily skilled artisan would have had a reasonable expectation of success because CN’460 teaches the (G4S)4 linker as an alternative for joining light and heavy chain variable regions. It would have further been obvious to omit the C-terminal lysine as Douillard teaches that this lysine is frequently clipped during the production of antibodies and demonstrates that an antibody with or without a C-terminal lysine provided similar results. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached on 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693