DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-18, 20, and 23-26 are pending and under examination.
Claim Objections
Claims 1 and 10 are objected to because of the following informalities:
Claims 1 and 10 state: “a central nervous system of a subject” and “wherein said central nervous system is selected from the group consisting of…” However, humans, mice and other vertebrates have a single central nervous system. An example of language that would overcome the objection to claim 10 would be: “wherein the myeloid cells are administered into the central nervous system at a location selected from intracerebroventricular (ICV) space, brain, spinal cord, cerebrospinal fluid (CSF), and intraparenchymal space.”
Appropriate correction is required.
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 6, 8, and 14 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 6, dependent of claim 2, recites the limitation "said inherited metabolic disorder".
Claim 8, dependent on claim 2, recites the limitation "said inherited metabolic disorder".
Claim 14, dependent on claim 1, recites the limitation "the accumulated undegraded substrate".
There is insufficient antecedent basis for these limitations in the claim.
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.
WRITTEN DESCRIPTION
Claims 1-18, 20, and 23-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
The teachings of the specification and the claimed invention
The invention is directed to a method of treating a metabolic disorder comprising administering myeloid cells into the central nervous system of a subject to be treated. Claim 1 is broadly directed to any metabolic disorder, any myeloid cell type, any enzyme and any substrate. The claim as written does not require that metabolic disorder, the enzyme or the substrate are related in any way.
The specification provides very specific examples of this invention distilled to practice. Pertaining to the metabolic disorder, the specification is directed exclusively to lysosomal storage diseases (Pg. 1, paragraph [0003]). Example 3 exemplifies the method for use in IDUA (alpha-L-iduronidase) knockout mice model of Hurler Syndrome and GUSB (Beta- glucuronidase) knockout mice model of Sly Syndrome (Pg. 26, paragraph [0105]). Example 5 is directed to myeloid treatment in a juvenile immunocompromised mouse model of Krabbe disease (Pg. 32, paragraph [0134]).
The myeloid cells disclosed in the specification are generated from human iPSCs and differentiated to the myeloid lineage in culture (Pg. 34, “Myeloid Cell Differentiation Protocol”). The resulting cells have a CD45+CD14+CXCR3+ phenotype. Importantly, the specification teaches the following functional characteristic of the specific myeloid cells of the disclosure: the myeloid cells engrafted in the brain parenchyma express the canonical microglial marker TMEM119 and have assumed a resting microglia identity (Fig. 29), the engrafted myeloid cells upregulate microglial signature genes (Fig. 33).
The state of the relevant art
The state of the relevant art is such that the term “myeloid cell” encompasses a heterogenous population of cells, including granulocytes, monocytes, macrophages, and dendritic cells. Yáñez (Curr Opin Hematol. 2022 Jul 1;29(4):201-208) teaches the factors that determine the diversity among myeloid cells are ontogeny with specific subsets of myeloid cells arising from distinct progenitors and secondarily, microenvironmental cues (see Abstract).
The specification teaches the use of specific subset of myeloid cells suitable for use in the claimed methods, but does not offer guidance as to how to identify other myeloid cells known in the art that could also be used in the methods.
Claim analysis
In view of the teachings of the instant invention and the state of the relevant art, the instant claims have the following written description issues:
Claim 1:
The method comprises administering myeloid cells, which encompasses a diversity cell types and origins, however the specification only discloses the use of myeloid cells differentiated from human pluripotent stem cells for use in this method.
The method claims the following function: “allowing the administered myeloid cells to engraft and to produce an enzyme”, but without providing a specific identity of the cells it is not clear how one can know what kind of myeloid will engraft and produce an enzyme.
The claim states that engrafted myeloid cells will produce an enzyme, but the enzyme or class of enzyme is not disclosed, and it is not clear if the production of the generically claimed enzyme is the mechanism by which the disorder is treated.
The claim requires monitoring the amount of the substrate of a sample to determine the progress of the treatment, but does not state how the substrate is monitored and how progress of the treatment is determined.
Therefore, claim 1 and all dependent claims are rejected under 35 U.S.C. 112(a) for being dependent on claim 1 and not providing limitations that overcome the written description rejection.
SCOPE OF ENABLEMENT
Claims 1-18, 20, and 23-26 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 lysosomal storage diseases with myeloid cells generated from iPSC, does not reasonably provide enablement for a method of treating any metabolic disease with any myeloid cell. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and the nature of the invention
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed method is that injection of any myeloid cell into the central nervous system of a subject can treat any metabolic disorder.
The state of the relevant art
The state of the relevant art is such that not all myeloid cells are enabled for treating metabolic diseases in the brain. The term “myeloid cells” encompasses platelets, erythrocytes, granulocytes (neutrophils, eosinophils, basophils), monocytes/macrophages, and dendritic cells (Weiskopf, Microbiol Spectr. 2016 Oct;4(5):10, Fig. 1). The term “PBMC” as disclosed in claim 4 comprises both lymphoid and myeloid cells with monocyte population comprising only 22.7% (STEMCELL Technologies, Human Peripheral Blood Mononuclear Cells, Pg. 3, Fig. 1).
Pertaining specifically to macrophages, Chen (Med Rev (2021). 2023 Nov 1;3(5):381-407) teaches when macrophages infiltrate the spinal cord after nerve injury, they release cytokines, chemokines, and reactive oxygen species causing nerve damage (Pg. 382, Full paragraph 1, Left column, Lines 9-17).
Though macrophage cell-based therapies exist, the art to date does not teach the administration of macrophages directly into the CNS, as reviewed by Na (Exp Mol Med. 2023 Sep;55(9):1945-1954) who teaches macrophage injections locally at ulcers, intrathecal introduction of M2 macrophages, i.v. infusions of regulatory macrophages, and intraperitoneal infusion of mesothelin macrophage CARs (Table 1).
Importantly, cells suited for the instant invention are required to engraft into the brain and differentiate into microglia, as taught for example, in US2020/0338132 ([0002]) who show that injection of progenitor cells results in microglial differentiation and engraftment. In contrast, Cronk (J Exp Med. 2018 Jun 4;215(6):1627-1647) teaches macrophage engraftment is only induced in the context of persistent microglial loss (Pg. 1628, Right column, Full paragraph 1, Lines 4-9, Fig. 1F).
In total, the art teaches the unpredictability in determining the cell types suitable for engraftment into the brain and treatment of metabolic disorders.
The amount of direction provided by the inventor and the existence of working examples
What is enabled by the working examples is narrow in comparison to the breadth of the claims. The working examples disclosed in the specification that exemplify the claimed method are limited to a single source of myeloid cells and three lysosomal storage disorders and thus does not provide enabling guidance for the methods as broadly claimed.
In view of the lack of the predictability of the art to which the invention pertains, the lack of guidance and direction provided by applicant, and the absence of appropriate working examples commensurate with the scope of the claims, undue experimentation would be required to use the claimed invention.
The quantity of experimentation needed to make or use the invention
The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating metabolic disorders. Therefore, claim 1 and dependent claims are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
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.
Claims 1-2, 5-17, and 23-26 are rejected under 35 U.S.C. 103 as being unpatentable over Biffi (US2020/0038439A1, published 02/06/2020, IDS 05/24/2023), in view of Douvras (US2017/0253856A1, 09/07/2017, IDS 05/24/2023) and Kubaski (Diagnostics (Basel). 2020 Mar 16;10(3):161).
The disclosure of Biffi is directed to compositions and methods for the treatment of a lysosomal storage disorder by reconstitution of brain myeloid cell and microglia upon transplantation of hematopoietic cells enriched in microglia reconstitution potential (see Abstract).
Regarding claims 1 and 10, pertaining to a method of treating a metabolic disorder comprising administering myeloid cells into the central nervous system of a subject (claim 1), specifically the intracerebroventricular space (claim 10), Biffi teaches intra-cerebral ventricular injection of hematopoietic stem cells into a subject and subsequent engraftment of the cells and differentiation to the myeloid lineage, CD45+CD11b+ (Pg. 43 claim 1 and Pg. 44 claim 37, Fig. 1B and 1C)
Regarding claims 5, 6, 8 and 25-26, wherein said metabolic disorder is an inherited metabolic disorder (claim 5), specifically a lysosomal storage disease (claim 25), and more specifically Hurler syndrome (claim 6, 26) or Sly Syndrome (claim 8, 26), Biffi teaches the methods are intended for treating inherited lysosomal storage disease including Hurler syndrome and Sly syndrome (Pg. 14, Table 1).
Regarding claims 7 and 9, wherein said enzyme is alpha L-iduronidase (IDUA) (claim 7) or beta-glucuronidase (GUSB) (claim 9), Biffi teaches the defective enzymes in Hurler and Sly syndomes are IDUA and GUSB, respectively (Pg. 14, Table 1).
Regarding claim 11, wherein said subject is a mouse or human, Biffi teaches the “subject” of the disclosure includes humans and non-human mammals ([0054], Lines 1-5).
Regarding claim 12 and 14, wherein said substrate is glycosaminoglycans (claim 12) and wherein said enzyme is used to reduce the accumulated undegraded substrate (claim 14), Biffi teaches the incompletely degraded substrate of mucopolysaccharidoses lysosomal storage diseases, such as Hurler syndrome, are glycosaminoglycans ([0136], Lines 1-3) where an increase of enzyme produced by engrafted cells would inherently reduce the undegraded substrate.
Regarding claims 13, 23, and 24, wherein said subject to be treated has an accumulation of undegraded substrate in cells of the subject (claim 13), specifically cells in the brain (claims 23 and 24), these properties are inherent to the lysosomal storage disorders, Hurler syndrome and Sly syndrome as evidence by Biffi who teaches lysosomal disorders result in accumulation of incompletely degraded substrates in the CNS ([0130], Lines 1-12).
The disclosure of Biffi does not teach (1) the cells administered into the CNS are myeloid, (2) the myeloid cells are pluripotent stem cell-derived, or (3) monitoring of the levels of enzyme and substrate in serum, urine or cerebrospinal fluid, and comparison to a healthy sample.
These deficiencies are taught by Douvras and Kubaski.
The disclosure of Douvras is directed to methods and compositions for the generation of microglial progenitor cells and microglial cells from pluripotent stem cells (see Abstract). Douvras established a feeder-free protocol to differentiate human pluripotent stem cells toward the myeloid lineage ([0072], Lines 3-5 and Fig 1A). Their iPSC-derived microglia resembled human primary microglia as compared through transcriptome analysis ([0075]-[0077]).
Regarding the limitation of claim 1 and claim 2, wherein the cells administered into the CNS are myeloid cells (claim 1) and wherein said myeloid cells are pluripotent stem cell (PSC)-derived myeloid cells (claim 2), Douvras teaches a method of treatment comprising administering PSC-derived microglia of the disclosure to a subject having a disease or disorder associated with a defect in or deficiency of microglial or microglial progenitor cells (Pg. 16, claim 21).
The disclosure of Kubaski is directed to the clinical manifestations, laboratory diagnosis, and therapeutic approaches for mucopolysaccharidosis type I lysosomal storage diseases (Pg. 2, Full paragraph 5).
Regarding the limitation of claim 1 wherein the method comprises monitoring the level of the enzyme in a serum sample, a urine sample or a cerebrospinal fluid sample of the subject to be treated; and monitoring the amount of a substrate in the serum sample, a urine sample or a cerebrospinal fluid sample, Kubaski teaches quantification of the substrate glycosaminoglycan in urine, serum, and cerebrospinal fluid (Pg. 5, Full paragraph 1, Lines 1-4) and measurement of residual activity of alfa-L-iduronidase enzyme with an ezyme assay in plasma (Pg. 5, Full paragraph 3, Lines 1-4). These measurements can be used to monitor response to treatment.
Regarding claim 15, wherein a sustained reduction in total substrate levels greater than about 20% is indicative of successful treatment of said metabolic disorder, this limitation is an intended use of the method of measuring substrate levels as taught by Kubaski.
Regarding claims 16 and 17, wherein the amount of enzyme (claim 16) and activity of enzyme (claim 17) in the serum sample is compared to the amount of enzyme in the serum sample of a healthy subject, Kubaski Fig. 3 teaches that enzyme testing is compared to reference range, which is reasonably interpreted as a reference range established in healthy subjects (Pg. 6, Fig. 3).
It would have been obvious to one having ordinary skill in the art to modify the teachings of Biffi with the teachings of Douvras and Kubaski by (1) administering microglia-like myeloid cells into the CNS (2) deriving the myeloid cells from pluripotent cells, and (3) monitoring of the levels of enzyme and substrate in serum, urine or cerebrospinal fluid, and comparison to a healthy sample. One would be motivated to do so because Biffi teaches the administration of HSPCs that differentiate into microglia and engraft in the brain and (1) Douvras teaches in vitro generation of microglia from human pluripotent cells, such cells suitable for engraftment into the brain and (2) Kubaski teaches known methods of diagnosing and monitoring lysosomal storage diseases by measuring substrate and enzyme and comparing to reference samples. There would be an expectation of success in modifying Biffi’s methods because Douvras validates that their protocol produces myeloid lineage cells and Kubaski teaches methods of monitoring disease that are standard in the field. The cells of Douvras, which are more differentiated that those of Biffi’s could readily be substituted into the treatment method.
Claims 1-2, 5-18, 20 and 23-26 are rejected under 35 U.S.C. 103 as being unpatentable over Biffi (US2020/0038439A1, published 02/06/2020, IDS 05/24/2023), in view of Douvras (US2017/0253856A1, 09/07/2017, IDS 05/24/2023) and Kubaski (Diagnostics (Basel). 2020 Mar 16;10(3):161). as applied to claims 1-2, 5-17, and 23-26 above, and further in view of Hofman (Front Neuroanat. 2014 Mar 27;8:15).
The combined teachings of Biffi, Douvras, and Kubaski do not teach that the amount of cells to be injected in a human is in the range of about 25 x 106 to about 1250 x 106 (claim 18) or about 100 x 106 to about 500 x 106 cells.
These deficiencies are taught by Hofman.
The disclosure of Hofman is directed to a review of the comparative studies of mammal brains (Abstract). Hofman teaches the mouse brain volume is 0.5 cm3 and human brain is 1400 cm3 (Pg. 2, Right column, Full paragraph 2, Lines 4-6).
Regarding claims 18 and 20, wherein the amount of said cells to be injected in a human is in the range of about 25 x 106 to about 1250 x 106 (claim 18) or about about 100 x 106 to about 500 x 106 cells (claim 20), Biffi teaches intracerebroventricular injection of 3x105 cells into mice and Hofman teaches the ratio of brain volumes between human and mice is 2800. Therefore a human injection scaled based on brain parenchyma volume would equate to 840 x 106 cells, which reasonably meets the limitation that the administration is about 25 x 106 to about 1250 x 106 and about 100 x 106 to about 500 x 106 cells.
It would have been obvious to one having ordinary skill in the art to modify the combined teachings of Biffi, Douvras, and Kubaski with the teachings of Hofman by administering about 25 x 106 to about 1250 x 106 or about 100 x 106 to about 500 x 106 cells in a human subject. One would have been motivated to do so because Biffi provides guidance as to optimal dosage for IVC injection in a mouse model and Kubaski teaches the relative brain volume between humans and mice which provides a starting point for determining effective human dosing. There would be an expectation of success because persons having skill in the art would understand that determination of an effective amount of cells in the method requires routine experimentation, which would reasonably involve extrapolating the equivalent dose from mouse to human based on brain volume.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 1-18, 20, and 23-26 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-18, 20, and 23-26 of copending Application No. 18/835,231 (reference application). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Conclusion
No claims are allowed.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646