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 .
This office action is in response to the paper filed on 01/07/2026. Claims 1-40 were previously presented. Claims 1-39 have been withdrawn, claims 41-80 have been added. Accordingly, claims 40-80 are currently under consideration.
Election/Restriction
Applicant’s election without traverse of the inventions of Group IV, (Claim 40 and newly added claims 41-80) and the following species: SEQ ID NO: 827, drawn to a single species of an engineered polynucleotide sequence in the reply filed on 01/07/2026, is acknowledged.
Applicant argues that the methods of claims 60-80 should be considered in this application due to the commonality of the subject matter. Applicant argues the method of claims 60-80 are similar except that the leucine decarboxylase peptide defined in claim 40 is itself administered to the subject rather than a polynucleotide encoding said leucine decarboxylase peptide.
Applicant’s arguments are not persuasive because the elected invention is drawn to a gene therapy method comprising administering a polynucleotide, while the withdrawn claims are drawn to a polypeptide-based method, each belonging to different CPC classes. The mode of administration and considerations of a method comprising a nucleic acid are materially different from those of the administration of a polypeptide.
Therefore, claims 60-80 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/07/2026.
Applicant is reminded that upon the cancelation of a claim to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and the processing fee required under 37 CFR 1.17(i).
Claims 40, 43, 44, and 50-59 are currently under the examination on the merits.
Priority
This application claims priority to the provisional application 62/970,039, with an effective filing date of 02/04/2020.
Claim Interpretation
With regards to claim 40 of the instant application, the claim “a method for treating and/or preventing the symptoms of maple syrup urine disease in a subject (MSUD), comprising administering to a subject having MSUD, a pharmaceutical composition comprising a polynucleotide sequence encoding a leucine decarboxylase polypeptide comprising a sequence at least 90% identical to SEQ ID NO: 766” reads as any polynucleotide sequence that encodes any polypeptide that has at least 90% identity to SEQ ID NO: 766. With regards to method, method of administration can include any suitable means known in the art, but not limited to parenteral, oral, topical, transdermal, etc. (see paragraph 0153 of the specification) since the specification does not have a limiting definition. Treating and/or preventing of the symptoms of MSUD is interpreted as direct alleviation of symptoms associated with MSUD or wherein administration prevents the appearance of symptoms entirely in a subject with MSUD. Subject refers to a male or female mammals such as humans, non-human primates, livestock, companion animals, and laboratory animals (see paragraph 0036 of the specification).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 40-59 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claim recite a method for treating and/or preventing the symptoms of maple syrup urine disease in a subject, comprising administering to a subject with the disease a pharmaceutical composition encoding a leucine decarboxylase polypeptide comprising any polynucleotide sequence wherein the polypeptide is at least 90% identical to SEQ ID NO: 766, which would encompass a genus of polynucleotides that would encode proteins where up to 39 amino acids could be modified by addition, deletions or modification to the sequence of SEQ ID NO 766 Further claims recite an engineered leucine decarboxylase having specific position mutations of SEQ ID NO: 766, as well as specific position and amino acid modifications compared to SEQ ID NO: 12, which is described as a WT variant of leucine decarboxylase isolated from Plancytomycetaceae bacterium with improved leucine activity, low pH tolerance, and protease resistance (see paragraph 0171).
Regarding the variants of engineered LDC, the instant specification discloses amino acid positional differences compared to SEQ ID NO: 12 and 766 as well as leucine enzyme activity normalized fold change over improvement of positive control (FIOP) of variants. Applicant does show some variants having greater leucine decarboxylase activity relative to SEQ ID NO:12 and 766, evidence provided from Table 2.1, 3.2, 4.1, 5.1, 6.1, 7.1, 8.1, 8.2, 10.1, 11.1, and 11.2 of the specification, but these experiments are done in vitro.
However, applicant only discloses 3 SEQ ID NOs for in vivo characterization of engineered leucine decarboxylases (SEQ ID NO: 484, 686, and 766, see paragraph 0196). For this experiment, applicant uses iMSUD mice and healthy cynomolgus monkeys. In the case for the monkeys, healthy monkeys do not read on claim 40 which recite the subject having MSUD. Furthermore, for the iMSUD mice model, applicant only shows a significant reduction of plasma leucine, but no evidence that phenotypic symptoms of MSUD are alleviated or prevented (see examples 12 and 13 of the specification).
Taken together, it is clear that the applicant does not have possession of all embodiments of the invention as claimed. Applicant only tests 3 engineered leucine decarboxylases in vivo but not all leucine decarboxylases encoded by a sequence with at least 90% identity to SEQ ID NO: 766 nor the limitations of claim 41 which recites at least one substitution compared to SEQ ID NO: 12. Furthermore, the specification only teaches reduction of plasma leucine in vivo for the 3 engineered leucine decarboxylases, but makes no claims on whether it prevents or treats MSUD in a subject with the disease. Applicant have not described sufficient number of polynucleotides that encoding a leucine decarboxylase with at least 90% identity to SEQ ID NO: 766 or a leucine decarboxylase with the amino acid substitutions relative to SEQ ID NO: 12, by describing complete structure or testing their activity in vivo in a subject with MSUD or in an animal model.
In view of the foregoing, it is concluded that the instant specification fails to adequately describe the claimed method in such a way as to reasonably convey to one skilled in the relevant art that the instant co-inventors had possession of the claimed invention at the time the application was filed.
Enablement
Claims 40-59 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosure in the specification coupled with information known in the art without undue experimentation (United States vs Telectronics, 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor bur rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant Wands factors are indicated below:
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
The nature of the invention;
The breadth of the claims;
The state of the prior art;
The level of skill in the art;
The level of predictability in the art;
The amount of direction provided by the inventor;
The presence or absence of working examples;
The quantity of experimentation necessarily needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
Further MPEP §2164.01(c) recites, “When a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation. See In re Vaeck, 947 F.2d 488, 495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991) (claiming a chimeric gene capable of being expressed in any cyanobacterium and thus defining the claimed gene by its use).”
Claim 40 recites a method for treating and/or preventing the symptoms of maple syrup urine disease (MSUD) in a subject with the administration of a pharmaceutical composition comprising a polynucleotide sequence encoding a leucine decarboxylase. Claims 41-59 are dependent on claim 40.
Based off the information disclosed in the specification of the instant application, treating and/or preventing encompasses preventative and palliative treatment (paragraph 0106) in order to prevent or delay the onset of symptoms. Symptoms, as disclosed in the specification, is not fully defined. Applicant discloses characteristics of the disease in newborns such as poor feeding, vomiting, lethargy, abnormal movements, and delayed development, however, no specific symptoms that the method seeks to ameliorate are mentioned. A pharmaceutical composition is not fully defined, other than it can comprise of standard pharmaceutical carriers, buffers, and excipients (paragraph 0101). Furthermore, a subject refers to mammals such as humans, non-human primates, livestock, companion animals, and laboratory animals, both male and female (paragraph 0094).
Regarding these claims, applicant discloses in the specification, Table 12-1 and Table 13-1 which shows percentage reduction in plasma leucine in healthy cynomolgus monkeys and iMSUD mouse model in response to a whey protein meal, respectively. For the case of the iMSUD mouse model, which expresses an intermediate form of MSUD, applicant does not disclose the effects of the reduction in plasma leucine or how this ameliorates the effects of MSUD.
Nature of the Invention
The claimed invention directs to a method of treating and preventing the symptoms of MSUD in a subject through the administration of a pharmaceutical composition comprising a polynucleotide. In this case, a subject can embody a male or female mammals such as humans, non-human primates, livestock, companion animals, and laboratory animals. Treatment and prevention is defined as preventing or delaying the signs of symptoms and where, in some embodiments, the subject is able to eat a diet that is less restricted in its isoleucine, leucine, and/or valine content (paragraph 0036). The characteristics of the disease is described, and therefore, could be interpreted as the symptoms such as poor feeding, vomiting, lethargy, abnormal movements, and delayed development.
Thus, the claimed invention requires reliable method of administering a polynucleotide that encodes an engineer leucine decarboxylase so that polynucleotide is delivered to appropriate target cells such that the polynucleotide is expressed in the cells, sufficient amount of the decarboxylate is produced that is sufficient to improve the symptoms of MSUD or prevent the symptoms from showing in the first place.
The Breadth of the Claims
The scope of claim 40 and dependent claims 41-59 encompasses treatment and symptom prevention of MSUD. Treatment and prevention could be understood as either eliminating symptoms or showing an improvement in the health of a subject, or the prevention and onset of symptoms entirely. A pharmaceutical composition can refer to any acceptable pharmaceutical composition for suitable use in subjects. Subjects are defined as mammals such as humans, non-human primates, livestock, companion animals, and laboratory animals, both male and female (paragraph 0094). Applicant claims any polynucleotide encoding any engineered leucine decarboxylase that has 90% identity to SEQ ID NO: 766.
Guidance of the Specification
The specification does disclose the percentage reduction in Plasma leucine levels, relative to area under the curve compared to vehicle or control, when an engineered LDC is administered to iMSUD mice and healthy non-human primates. The specification does not disclose whether the percentage reduction resulted in characterizable symptom relief, nor does it test preventative care. Furthermore, the specification dose disclose dosage to subjects through oral administration (see paragraph 0195).
The State of the Art
At the time of the instant application, the only treatment available for MSUD was diet monitoring, liver transplantation, and some studies looking at sodium phenylbutyrate (see treatment options section)(Blackburn et al, Maple syrup urine disease: mechanisms and management, The Application of Clinical genetics, Volume 10, Issue 2017, all pages, 09/06/2017). Blackburn discloses that orthotopic liver transplantation in pediatric patients with class MSUD has been a very successful treatment (see treatment options), however, restricted diet to avoid BCAAs is still the most prominent form of management. At the time of filing of the instant application, there was no teaching of administering a polynucleotide that encodes a leucine decarboxylase polypeptide comprising a sequence at least 90% identical to SEQ ID NO: 766 to a patient of MUSD or any other related animal model or system.
In a post-effective filing date art, Skvorak et al (Oral enzyme therapy for maple syrup urine disease (MSUD) suppresses plasma leucine level in intermediate MSUD mice and healthy nonhuman primates, JIMD, Volume 46, Issue 6, Pg. 1089-1103) discloses the use of engineered leucine decarboxylase enzyme, generated from site saturation mutagenesis, as a form of oral therapy (see introduction) in order degrade dietary leucine when administered to iMSUD mice and healthy cynomolgus monkeys. Skvorak teaches that after oral administration of an engineered LDC, leucine spike and the incremental area under the curve (iAUC) was suppressed by 30-59% depending on which engineered LDC was used (see section 2.4). Mice treated with LCDv10 maintained plasma leucine at or below their baseline levels out to day 14. At day 14, vehicle-treated animals appeared hunched and unkempt, classic indicators of illness in mice and specifically in this model compared to LDCv10-treated mice which did not display any visual symptoms of the disease. In order to better test a model to replicate the human GI tract, healthy nonhuman primates were used where treatment with LDCv10 suppressed the spike in leucine after the high-protein meal.
Skvorak does not teach administering any polynucleotide encoding a polypeptide with 90% identity to SEQ ID NO: 766 and where this treatment can be applied to any subjects with symptoms associated with MSUD. The two test models were healthy primates, without MSUD and a mice model with intermediate MSUD. Skvorak does not disclose whether this can be used to prevent MSUD in the first place. While Skvorak discloses that this approach may represent a broader opportunity for engineering amino acid-degrading enzymes, Skvorak does not provide any guidance regarding administering any polynucleotide sequence encoding for a leucine decarboxylase polypeptide with 90% identity to SEQ ID NO: 766(see discussion).
The Level of Predictability in the Art
The level of predictability in the art is considerably low. Prior to the filing date, treatment of MSUD is disclosed as diet management for BCAAs or a liver transplant. Post-filing art shows that an oral engineered enzyme reduced phenotypic symptoms of disease in iMSUD mice, although it does not disclose these symptoms are directly related to MSUD (see Skvorak et al.).
The art of delivering drugs, including nucleic acids, is challenging with regards to genetic diseases. In the specification, applicant details oral administration where in the composition is in the form of a pill, tablet, capsule, gelcap, liquid, or emulsion (see paragraph 0035). The post filing date art of Skvorak also details oral administration to subjects. According to Kumari et al. (Oral Delivery of Nucleic Acid Therapies for Local and Systemic Action, Pharmaceutical Research, Volume 40, Pg. 107-122, 2022), intravenous or intramuscular formulations constitute majority of marketed formulations containing nucleic acids. Though oral administration is traditionally preferred due to ease of administration as well as higher patient compliance, oral delivery adds another set of biological and physiochemical barriers to efficient and targeted delivery (see abstract and introduction (Kumari)). Targeted delivery of payloads such as drugs, NAs, or peptides when administered via oral route is challenging if the target is beyond the gastrointestinal tract (GIT), and most effective for diseases such as IBS or Chron’s disease (see section Mechanism of Oral Absorption of NAs (Kumari)). Challenges include dealing with the degradation of nucleic acids due to the pH and enzymatic load of the GIT, mucus, the epithelial lining, and peristalsis (See section Challenges to Oral Delivery of NAs (Kumari)), wherein nucleic acids would have to bypass these barriers and systematically proliferate throughout the subject. Kumari concludes that while there are studies that show successful oral delivery of NAs in preclinical animal models, these tend to be related to GIT diseases and the success of the administration of nucleic acid therapy orally is uncertain.
Furthermore, Skvorak details that differences in mouse and human metabolic rate make translation to the human condition (of MSUD) difficult. In contrast, healthy cynomolgus monkeys have greater similarities with the human GI tract in terms of transit times, volumes, and metabolic rate (see section 2.5 of Skvorak). However, a healthy subject does provide support of claim 40, wherein the subject has MSUD.
The Presence or Absence of Working Examples
At the time of the effective filing date, there is no prior art that discloses a method for the treatment and/or prevention of symptoms associated with MSUD where a pharmaceutical composition comprising a polynucleotide encoding a leucine decarboxylase is administered. In the specification, the applicant only discloses 3 examples of an engineered leucine decarboxylase administered to a subject (a mouse model) with MSUD, which is far short of the multitude of leucine decarboxylase variants claimed in the instant application. Skvorak does show an oral engineered leucine decarboxylase enzyme for the treatment of MSUD, however, Skvorak only tested one variant, LCDv10 (see introduction), which again, is limiting compared to any leucine decarboxylase with 90% identity to SEQ ID NO: 766 encoded by a polynucleotide.
The Quantity of Undue Experimentation
In light of the limited amount of research into testing a method of administering a pharmaceutical composition comprising a polynucleotide encoding engineered leucine decarboxylase for treating and/or preventing MSUD in a subject, including humans as a subject, the quantity of experimentation necessarily needed to use the invention as claimed is considerably high.
One skilled in the art would have to conduct extensive experiments to show that all the all polynucleotide sequences encoding a modified leucine decarboxylases, with at least 90% identity to SEQ ID NO: 766, could be formulate in a pharmaceutical composition, and then administered to a subject, which includes humans, and there is a notable reduction of symptoms, or a prevention of symptoms all together of MSUD.
Conclusion of 35 U.S.C. 112(a) Scope of Enablement Analysis
After applying the Wands factors and analysis to claims 40-59, taking into the consideration the factors outlined above, it is concluded that the specification is not enabled. This is because the specification does not disclose any evidence that the method of administering a pharmaceutical composition comprising a polynucleotide encoding a leucine decarboxylase polypeptide to a subject, especially a human subject, would result in treating or preventing the symptoms of MSUD. The specification only discloses a reduction in plasma leucine in healthy cynomolgus monkeys and iMSUD mice when a composition was administered by oral gavage.
Furthermore, prior to and after the time of the instant application, the state of the art of treating and/or preventing MSUD in a subject by administering a pharmaceutical composition with a polynucleotide encoding a leucine decarboxylase was immature. The state of the art, post filing, shows evidence that iMSUD mice treated with an engineered leucine decarboxylase displayed no physical symptoms of illness, such as appearing hunched and unkempt, but this does not read on the direct symptoms of MSUD such as sweet, syrup smell in urine, lethargy, nor more extreme symptoms such as neurological complications and metabolic decomposition (see abstract of Blackburn). Applicant would need to show that all claimed LDC variants could be administered to treat and prevent MSUD in a subject, including humans.
Applicant only tested 3 LDC variants (SEQ ID NOs: 484, 686, and 766) for plasma leucine reduction in an in vivo subject. However, this does not support enablement because a reduction in plasma leucine levels do not enable treating and/or preventing the symptoms of MSUD as described above in Blackburn, symptoms being sweet smelling urine, lethargy, neurological complications and metabolic decomposition. Tests of other variants were done in vitro to show relative enzymatic activity compared to wild type, listed as SEQ ID NOs in Tables 1-8, however, that is not sufficient to support enablement because the enzymatic activity of a polypeptide encoding an engineered leucine decarboxylase does not provide any evidence on whether these enzymes can be administered to a subject, wherein the effects of administration can be observed.
Regarding claims that recite 90% identity, Applicant would need to provide a sufficient number of variants with at least 90% identity to SEQ ID NO: 766 as recited in claim 40 representative of the entire genus, in vivo, including the elected species SEQ ID NO: 828, and show how these subjects exhibit either an improvement or prevention of symptoms related to MSUD.
In view of the breadth of the claims, the state of the art of treating and/or preventing MSUD, the unpredictable nature of oral nucleic acid drug delivery, and the lack of working examples of the invention and, the information disclosed in the specification, one skilled in the art would have had to perform undue experimentation in order to practice the invention commensurately with the claimed scope. Therefore, claims 40-59 are rejected under 35 U.S.C. 112(a) for failing to disclose sufficient information to enable a person of skill in the art to use the invention commensurate in scope with these claims.
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID YU whose telephone number is (571)272-1118. The examiner can normally be reached Monday-Friday 7:30 am -5 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.T.Y./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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