DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment of 8/24/26 has been entered in full. Claims 2 and 4-5 are canceled. Claim 1 is amended. Claims 1, 3, and 6-11 are pending.
Election/Restrictions
Applicants' election without traverse of Group II, currently all pending claims, in the reply filed on 8/24/26 is acknowledged. The subject matter directed to Group I has been removed by amendment.
The elections of the following species are also acknowledged: (1) human as the species of subject; (2) ALS as the species of neurodegenerative disease; and (3) allogeneic and HSCs as the species of modified bone marrow cells. Claim 7 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1, 3, 6 and 8-11 are under consideration, as they read upon the elected species.
Specification
The disclosure is objected to because of the following informalities:
---The title of the invention is not descriptive because it directed to any method of treating a neurodegenerative disease, but the claims are limited to treatment with a modified EKLF polypeptide. A new title is required that is clearly indicative of the invention to which the claims are directed. In view of the enablement rejection of the claims, the following title is suggested: “Methods of Treating Amyotrophic Lateral Sclerosis with a Modified EKLF Polypeptide”.
Appropriate correction is required.
Claim Objections
Claims 1, 3, 6 and 8-10 are objected to because of the following informalities:
In claim 1, line 8, “of lysine residue with arginine residue” should be “of a lysine residue with an arginine residue”
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a), enablement
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.
Claims 1, 3, 6 and 8-10 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
A method of claim 1, wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS), does not reasonably provide enablement for a method of claim 1 wherein the neurodegenerative is any other neurodegenerative disease.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The nature of the invention is a method with the intended purpose of preventing and/or treating a neurodegenerative disease (ND) in a human subject. This purpose is asserted to be achieved via a single method step which comprises administering an effective amount of a modified nucleic acid encoding a modified Erythroid Kruppel-like factor (EKLF) polypeptide, or modified bone marrow cells (BMCs) comprising said modified nucleic acid, wherein the modified EKLF comprises a substitution of lysine with arginine at position 54 of the wild-type EKLF polypeptide of SEQ ID NO: 3. The specification teaches that EKLF, “also named KLF1, is a Kruppel-like factor expressed in a range of blood cells” (¶ 33, published application), which can “[p]ositively or negatively regulate transcription through binding of its zinc finger domain to the CACCC motif of the regulatory regions of a diverse array of gene” (¶ 33) and which regulates erythropoiesis and differentiation of certain types of blood cells (¶ 33)
The claims are genus claims because they encompass treatment of multiple types of neurodegenerative disease (ND), with independent claim 1 broadly encompassing any type of ND, and dependent claim 11 further limiting the disease to one of six different NDs, including amyotrophic lateral sclerosis (ALS; the elected species under consideration); Lewy Body Dementia (LBD), Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS) or Huntington’s disease (HD).
In a review of treatments for neurodegenerative diseases (NDs), Duraes et al (2018) teaches that NDs “manifest themselves through mechanisms that are not fully understood, in many cases, and impair memory, cognition and movement” and that “[c]urrently, no [ND] is curable, and the treatments available only manage the symptoms or halt the progression of the disease” (see Abstract of Duraes et al, 2018. Pharmaceuticals. 11(44): pages 1-21). Duraes further teaches that NDs have “very different pathophysiologies” and that there is a “lack of understanding of the causes and mechanisms of these diseases, which leads to a lack of treatment” (page 2).
With respect to amyotrophic lateral sclerosis (ALS), Duraes teaches that “[t]he causes of ALS are of unknown aetiology in most cases, with about 10% being of genetic inheritance” (page 13). Duraes further teaches that the only treatments for ALS that are available are two drugs, riluzole and edaravone, that can “delay the progression of the disease” without reverting “the symptoms once they have manifested” (page 13).
The specification provides a working example in support of the use of the modified EKLF protein with regard to treatment of EKLF. Example 1 employs two different animal models of amyotrophic lateral sclerosis (ALS) to “examine the effect of Eklf (K74R) mutation on ALS”. In one model, the results demonstration “although the onset time the motor dysfunction of N390D/+/Eklf (K74R) mice was similar to that of the ALS control group, the behavioral ability of the N390D/+/Eklf (K74R) mice was significantly better than that of N390D/+ mice at eight months of age” (¶ 67, published application). In the other model, “indicated that 4 months post-BMT, the ALS mice receiving BMT from the Eklf (K74R) exhibited significantly better exercise ability than the control group” (¶ 68). The example concludes that administration of a nucleic acid encoding EKLF K74R or bone marrow cells expressing such will function in “alleviating or ameliorating the symptoms associated with ALS” (¶ 69).
While the results described in the working example provide support for the predictability in the use of the modified EKLF protein in treatment of ALS, it does not provide support for the treatment of the other neurodegenerative diseases (NDs), including the specific types listed in dependent claim 11, and thus fails to provide support for broader genus encompassing all NDs of independent claim 1. The specification does not provide any working examples directed to treatment of any other NDs. The specification does not provide any description of how the EKLF with the mutation functions to treat ALS in such a way that it would also function to predictability treat other NDs have different pathophysiologies as described by Duraes. While enablement does not necessarily require a working example, "[l]ack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art", per MPEP 2164.02. Furthermore, all of the currently known treatments taught by Duraes that treat the symptoms of different NDs are different compounds; for example, the treatments for delaying progression of ALS (e.g., riluzole) are not taught among the treatments taught for the other diseases. Thus, knowledge of one treatment for the symptoms of one ND (e.g., ALS) does not support the predictability of using such in the treatment of other NDs.
As such, at the time of filing of instant application the skilled artisan would not have predicted, based on the limited teachings of the prior art and the instant specification, whether the modified EKLF protein (EKLF K45R) could be used for treatment of NDs other than ALS. Before treating a patient with another type of ND with an ELKF K45R, the skilled artisan would first need to engage in a study of whether administration of the ELK K45R could actually treat such a ND, and such a study would be the focus of an entire paper in the relevant literature. Due to the large quantity of experimentation necessary to determine if one or more NDs other than ALS could be treated with a nucleic acid or cell encoding a modified EKLF (K45R) protein, the lack of direction/guidance presented in the specification regarding same, lack of working examples and the teachings of the prior art and the complex nature of the invention, undue experimentation would be required of the skilled artisan to use the claimed invention.
Claim Rejections - 35 USC § 112(a), written description
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.
Claims 1, 6 and 8-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Per MPEP 2163, 35 U.S.C. 112(a) requires, “separate and distinct from the enablement requirement”, that the “specification shall contain a written description of the invention…” (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010)). In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicants are claiming and what Applicants have possession of.
The claimed invention is directed to a method of treatment that employs a product, which is a nucleic acid encoding a modified ELKF polypeptide, or modified bone marrow cells comprising said nucleic acid. While the only expressly specified modification is a substitution of lysine with arginine at position 54 (K54R) of the wild type EKLF protein of SEQ ID NO: 3 (362 amino acids in length), Claim 1 broadly encompasses other mutations throughout the protein sequence. This is evidenced by dependent claim 3 (which is not included in this rejection), which expressly limits the modified EKLF to comprising the amino acid sequence of SEQ ID NO: 10, which is identical to SEQ ID NO: 3 but with the K54R mutation included. As such, parent claim 1 is broader in scope than this dependent claim and therefore encompasses other modifications to the EKLF protein of SEQ ID NO: 3. As such, the claims are directed to genus of modified EKLF proteins having the K54R mutation and one or more other mutations, without limit, such as other substitutions, additions and deletions with respect to SEQ ID NO: 3.
The prior art appreciates that "Mutations … are generally destabilizing, and can reduce protein … fitness" and "In general, more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation" (pg 602 of Tokuriki et al, 2009, Current Opinion in Structural Biology. 19: 596-604). The prior art also appreciates that "the range of possible SNV [single nucleotide variation] effects at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge" (pg 18 of Bhattacharya et al, 2017. Plos One. 12(3): e0171355, pages 1-22 as printed). Thus, knowledge of the sequence of a protein (e.g., the EKLF protein of SEQ ID NO: 10) is not sufficient for the skilled artisan at the time of the effective filing date to predict which mutations will result in a protein retaining the required activity to function in treatment of ALS.
Written description for a genus may also be satisfied through sufficient description of a relevant number of species. This is dependent on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus. Generally, in an unpredictable art, adequate description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Also, “[w]hen a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)). “[A] sufficient description of a genus … requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69).
A description of a single species that is defined by its amino acid sequence is not representative of a genus encompassing thousands or more members having different structures. Per MPEP 2163, "A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")
In the instant case, the specification provides very limited guidance as to the nature of which members of the large genus of variants of SEQ ID NO: 10 that are encompassed by claim 1 that will have the required functionality. The working example is limited to use of an EKLF protein having the amino acid sequence of SEQ ID NO: 10, i.e., the wild type protein of SEQ ID NO: 3 with a K54R mutation introduced. While a protein of SEQ ID NO: 10 has written description in and of itself, it does not provide any description of other sequences in the vast genus of encompassed mutant variants that retain the functionality of EKLF necessary for treatment of ALS.
The specification does not provide sufficient description to identify a representative number of species encompassed by the claimed genus by any method other than screening for additional members. However, as with antibodies, adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116).
Therefore, only a method of claim 1, wherein the modified EKLF polypeptide comprises the amino acid sequence of SEQ ID NO: 10, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112(a). Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (pg 1115).
Note on Prior Art Rejection(s)
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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, 6 and 8-11 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Shen et al, U.S. Patent Application Publication 2019/0282625, published 9/19/19, filed 9/13/17 and claiming priority to 9/13/16. The earliest date to which the instant application claims priority is 8/27/21.
Claims 1 and 11 each encompass a method of preventing amyotrophic lateral sclerosis (ALS) in a human subject by administering to the subject an effective amount of modified bone marrow cells encoding a modified Erythroid Kruppel-like factor (EKLF) polypeptide that comprises a substitution of lysine residue with arginine residue at amino acid position 54 of the a wild-type ELKF polypeptide of SEQ ID NO: 3. Prevention of a disease such as ALS does not require that the disease is present in the subject as the administered will treatment will prevent a subject from developing the disease.
Shen teaches “cells engineered with a gene encoding a ELKF polypeptide, which comprises at least one amino acid modification as compared to a wild type EKLF polypeptide, wherein the cell” is selected from a group including a HSC [hematopoietic stem cells]” (¶ 12). The bone marrow cells of instant claim 1 encompass HSCs as evidenced by instant dependent claim 6. Shen further teaches that the modification is “a substitution of Lys with Arg” at position 54 of the human EKLF polypeptide (¶ 13). Shen further teaches that the cells can be administered to “a recipient subject (e.g., a human” with the goal of “prolonging lifespan” (¶ 76-77). Because the administered product is the same as that of the instant claims, it would inherently produce the same effect when administered; i.e., prevention of ALS. As such, the teachings of Shen anticipate claim 1.
Claim 3 encompasses a method of claim 1 wherein the modified ELKF polypeptide comprising the amino acid of SEQ ID NO: 10, which is the sequence of the wild type gene of SEQ ID NO: 3 with the K54R substitution. The embodiment of Shen described above that anticipates claim 1 is directed to such an embodiment. As such, the teachings of Shen also anticipate claim 3.
Claim 6 encompasses a method of claim 1 wherein the modified BMCs comprise modified HSCs. The embodiment of Shen described above that anticipates claim 1 is directed to such an embodiment. As such, the teachings of Shen also anticipate claim 6.
Claim 8 encompasses a method of claim 1 wherein the modified BMCs are allogeneic. Shen further teaches that the transplanted cells of the instant can be allogeneic (¶ 40). As such, the teachings of Shen also anticipate claim 8.
Claim 9 encompasses a method of claim 8 further comprising the step of exposing the subject to a gamma irradiation prior to administered the BMCs. Shen further teaches exposing the subject to gamma irradiation prior to administering the HSCs (¶ 87). As such, the teachings of Shen also anticipate claim 9.
Claim 10 encompasses a method of claim 1 wherein the BMCs are intravenously administered. She further teaches intravenous administration of the cells of the invention (¶ 76). As such, the teachings of Shen also anticipate claim 10.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center to authorized users only. Should you have questions about access to the USPTO patent electronic filing system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via a variety of formats. See MPEP § 713.01. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/InterviewPractice.
/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674
Prosecution Insights