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 .
Claims 1-3 and 8-18 are pending. Claims 9-10, 14-15, and 17-18 are withdrawn from consideration as being directed to nonelected inventions or species.
Status of the Application
Applicant’s response and amendment filed 05 July 2025 are acknowledged and entered.
Applicant has amended Claim 1. Applicant has cancelled Claims 4-7.
Applicant has amended the Spec. and Drawings to overcome Objections; the objections are withdrawn.
Applicant has amended Claim 1 and cancelled claims 4-7 to overcome the 112(a) rejections; the 112(a) rejections are maintained but modified in response to the claim amendments.
Applicant has amended Claim 1 and cancelled claims 4-7 to overcome the 112(b) rejections; two 112(b) rejections are withdrawn but most of the 112(b) rejections are maintained but modified as necessary in response to the claim amendments.
Applicant has amended Claim 1 and cancelled claims 4-7 to overcome the 101 rejections; the 101 rejections are maintained but modified in response to the claim amendments.
Applicant has amended Claim 1 to overcome the 102 and 103 rejections; the 102 and 103 rejections are withdrawn.
Applicant has filed a terminal disclaimer (filed and approved on 05 July 2025) to overcome the NSDP rejections; the NSDP rejections are withdrawn.
Claims 1-3, 8, 11-13, and 16 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Claim Interpretation
The claims recite the term “applying”, for example in Claim 1: …applying the nucleic acid to a compound… The Spec. does not provide any definition for “applying” but it is interpreted as “physically applying the nucleic acid to…”. That interpretation is based on the Spec. disclosure (¶34):
Methods for applying nucleic acids of the present disclosure to various compounds may include: dissolving in solution, mixing, topically applying, and expressing in organisms. Other methods of applying nucleic acids may also be used without departing from the scope of the disclosure.
The term is interpreted as “physically applying” because all of those methods indicate some kind of physical contact between the nucleic acid and the protein.
The claims also recite the term “chaperone activity”. Wikipedia teaches that (“Chaperone [protein]”. Available online at wikipedia.org. Accessed on 01 April 2025, “Wikipedia”) chaperones (§Functions of molecular chaperones) can be holdases, foldases, disaggregases, assist in protein degradation, be involved in suppression of toxic protein oligomers via their clustering, and that new functions for chaperones continue to be discovered. Therefore the term “chaperone activity” is interpreted as possessing any of those functions including either “holdase” or “foldase” activity as discussed in the Spec. (¶5): Chaperones are a diverse group of proteins and other molecules that regulate proteostasis in the cell by preventing protein aggregation (holdases) and helping protein folding (foldases).
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.
Claims 1-3, 8, 11-13, and 16 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. This is a written description rejection. These rejections are maintained but updated in response to the claim amendments. All references are of record.
Claims 1-3, 8, 11-13, and 16 recite the following methods:
Claim 1: A method for providing chaperone activity to a protein-containing compound, the method comprising: selecting a nucleic acid based on one or more of the nucleic acid's particular properties and a specific sequence of the nucleic acid; and applying the nucleic acid to a compound comprising one or more proteins to provide chaperone activity to the compound, wherein the nucleic acid is a G-quadruplex nucleic acid comprising a specific sequence, the specific sequence comprising at least one of: Seq359 (SEQ ID NO:1), Seq536 (SEQ ID NO:2), Seq576 (SEQ ID NO:3), and wherein the chaperone activity comprises at least one of limiting protein aggregation and improving protein folding within the compound.
Claim 2: The method of claim 1, wherein the selecting comprises: selecting based on one or more of the nucleic acid's particular properties, the particular properties including at least one of efficacy of the nucleic acid's chaperone activity provided to the compound and the nucleic acid's effect on oligomerization.
Claim 3: The method of claim 1, wherein the selecting comprises: assessing efficacy of the nucleic acid's chaperone activity using TagRFP675.
Claim 8: The method of claim 1, wherein the applying comprises: providing chaperone activity to the compound, the chaperone activity comprising preventing protein aggregation within the compound and an amount of protein aggregation being within a range of under 60% of that of the protein alone as measured by turbidity at 360 nm.
Claim 11: The method of claim 1, wherein the selecting comprises: altering the specific sequence of the nucleic acid to improve chaperone activity within the compound.
Claim 12: The method of claim 11, wherein the altering comprises at least one of utilizing prior nucleic-acid-related knowledge and procedurally screening the nucleic acid.
Claim 13: The method of claim 1, further comprising reducing a disease state symptom utilizing the chaperone activity.
Claim 16: The method of claim 1, wherein the applying comprises: providing general chaperone activity to a plurality of proteins.
These broad claims encompass the following large genera:
Any nucleic acids having any particular properties and the specific sequence that comprises the claimed SEQ ID NOs 1-3,
Wherein the particular properties can include any effect on oligomerization and
Wherein the specific sequence can comprise any alteration; and
Any compounds comprising any tissue or any protein
that can be used to apply chaperone activity to a protein, wherein the chaperone activity is limiting protein aggregation or improving protein folding. Any kind of nucleic acid sequence comprising any one of the claimed SEQ ID NOs and possessing any particular properties and , and any compound comprising any tissue or any protein would be encompassed by the claims as instantly presented.
An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). 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, reduction to drawings, 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163.
The Spec. does not disclose structural properties of the claimed nucleic acids (i.e., the kinds of alterations to be applied) or the claimed compounds, tissues, or proteins commensurate with the breadth of the claims. The Spec. does not disclose how to modify the structures of the claimed nucleic acids comprising the SEQ ID NOs to produce or improve the claimed functions. Nucleic acids is a broad genus with diverse members and different structures that underly their function. Nucleic acid sequences (including those comprising quadruplex or G-quadruplex), nucleic acid sequences comprising the claimed SEQ ID NOs, and alterations to nucleic acid sequences are broad sub-genera with diverse members and different structures that underly their functions. Compounds, tissues, and proteins are similarly broad genus and subgenera with diverse members and different structures that underly their functions.
As discussed in §Claim interpretation and §112(b), many of the terms in the claims are indefinite. “Chaperone activity” has been interpreted as various activities, including “holdase” or “foldase” activity (See §Claim interpretation). The amended claims now limit that the chaperone activity is at least one of limiting protein aggregation and improving protein folding within the compound.
Compounds
The claims recite a method for providing chaperone activity to a protein-containing compound. Protein-containing compound encompasses a large genus of compounds and the subgenera of synthetic and natural protein-containing compounds. The Spec. discloses (¶32-33) a vast number of compounds encompassed by these terms, including literally any protein-containing compound or any substance produced by plants or animals.
Nucleic acids, chaperone activity, and general chaperone activity
The claims now require the chaperone activity is at least one of limiting protein aggregation (i.e., holdase activity) and improving protein folding (i.e., foldase activity) within the compound. The Spec. discloses (¶36) holdase activity may be highly sequence specific, with quadruplexes showing the greatest activity… several quadruplexes may display generality with potent holdase activity for a variety of different proteins. That passage does not disclose what portion(s) of the nucleic acid(s) is responsible for the holdase activity.
Regarding foldase activity, the Spec. discloses similar: (¶57-62 and ¶124-125) measuring the abundance of TagRFP675 (Fig. 16A-E) and wtGFP (Fig. 16G) fluorescence in the presence of known protein chaperones and some nucleic acid sequences to study their effect on foldase activity (i.e., more fluorescence indicates that the chaperone helped the expressed polypeptide sequence fold properly into a fluorescent protein). Those experiments led to the conclusion that (¶60-62 and ¶127) nucleic acid sequences comprising quadruplexes improve folding. However, even those examples report (¶59, ¶62) that any nucleic acid does not provide foldase activity to any protein—not even those comprising quadruplex sequences: Bulk nucleic acids may have little to no effect on GFP folding or aggregation and the acidic wtGFP was also tested and was less affected by the quadruplex-containing sequences. That indicates that certain structures within the nucleic acid(s) are required for chaperone activity, but the Spec. does not clarify what, specifically, those structures are, including what those structures are within the claimed SEQ ID NOs.
Although the Spec. describes that guanine content and G-quadruplexes have something to do with holdase and/or foldase activity, it does not identify any particular structure, including within the claimed SEQ ID NOs, that is responsible for that function. For example, the Spec. discloses the following information about sequence motifs and chaperone activity:
The Spec. teaches (¶41) holdase activity was found to be positively correlated with the guanine content in the sequences… analysis suggested that the most potent holdase activity was encoded by a polyG motif. The Spec. teaches (¶48) the type and stability of quadruplex conformation was shown to depend on the type of nucleic acid present (i.e., DNA or RNA). The Spec. teaches ¶52 shows specifically quadruplex DNA (as opposed to other DNA with higher level structure[s]) is required for holdase activity. The Spec. teaches (¶74) experimental results suggest that the topology of a quadruplex [i.e., parallel, anti-parallel, etc.] matters in its chaperone function, along with adjacent sequence. The Spec. teaches (¶127) the G-quadruplexes bind to TagRFP675 to help them fold, but also discloses (same ¶) it has not been determined whether this effect is …indirect (i.e., whether any other mechanism besides for G-quadruplexes binding to TagRFP675 to helps the fluorescent protein fold).
The Spec. teaches (¶51) using chemical denaturation aggregation assays in which the protein starts in a denatured state… data also suggests that the quadruplexes are binding a misfolded or partially denatured form of the protein rather than the native state, but no information is provided for what that misfolded or partially denatured form of the protein is or how to identify it or how the nucleic acid chaperone could be altered to modify chaperone activity.
The Spec. discusses (¶53) generality of G-quadruplex holdase activity using 14 G-quadruplex nucleic acid sequences and 10 ssDNA sequences on 4 proteins. Fig. 5A-E show a range of holdase activity. The Spec. teaches (¶55) their data strongly suggest that the holdase activity displayed by quadruplex sequences is general, while also unique to quadruplex-forming sequences but does not describe the specific G-quadruplex structure or portions of a structure that are responsible for the holdase activity.
The Spec. teaches (¶59) lack of aptamer effect on GFP folding or aggregation likely stems from electrostatic inhibition, as wtGFP is quite acidic, and would likely be repelled by the negative charge of the nucleic acids’ phosphate backbone but (¶60) TagRFP675 does not have that problem because it is more basic. That indicates that, contrary to Applicant’s claims, it would not be possible for any nucleic acid to provide chaperone activity—holdase or foldase activity—to any protein because if a nucleic acid cannot contact the protein, it cannot provide chaperone activity.
The Examples in the Spec. describe (¶37-130) only applying nucleic acids to a few purified proteins or to bacteria (which do not possess tissues). Most of the examples in the Spec. describe (¶39-54, Figs 1-5; ¶64-69, Figs 6-8; ¶74-78, Figs 10-12) applying nucleic acids to the protein citrate synthase (CS). Other examples are presented, wherein nucleic acids are applied to (¶54-55 and 64-69, Figs 5-6) the proteins luciferase, MDH, and LDH; (¶71, Fig 9) antibodies to IgG; (¶57-62 and ¶124-128, Figs 1516) TagRFP675 or wtGFP; and (¶120-124, Figs 13-14) Tau. That is a total of eight proteins. But the art of Perez-Iratxeta (et al. 2007. Towards completion of the Earth's proteome. EMBO Rep. 8[12]:1135-1141, “Perez”) teaches (§Abstract) there are approximately 5 million proteins on earth. Although the Spec. teaches that (§ starts at ¶53) some of their nucleic acid sequences exhibit general chaperone activity, and that (e.g., ¶41 and ¶127) guanine rich sequences are important for chaperone activity, the Spec. does not demonstrate that any of their nucleic acid sequences exhibits “general chaperone activity”, that any nucleic acid sequence can exhibit general chaperone activity, and does not identify any requisite structure—either on a nucleic acid sequence or on a protein target—that is necessary for the chaperone activity to occur.
Furthermore, as discussed above, there are at least two kinds of “chaperone” activity, namely holdase and foldase activities, and the Spec. does not disclose any specific structure requisite to either of them. The Spec. does not discuss other chaperone activities such as disaggregation or assistance with protein degradation or other new functions. Most of the examples discuss the effect of a nucleic acid sequence on holdase activity, and only (¶57-62 and ¶125, Fig 16) discuss any effect on foldase activity, and that is only for two proteins that are both fluorescent proteins, wtGFP and TagRFP675.
Altogether, there are many polyG motifs that comprise guanine and other bases in various orders and Applicant does not discuss any particular sequence of nucleotides that is responsible for the chaperone activity. Applicant themselves discloses (¶42) wide variability suggested that the motif required more than just high guanine content. The Spec. discloses that quadruplex structures are important for chaperone function and (¶74) the effect of some different topologies but does not disclose what nucleic acid sequences (including within the claimed SEQ ID NOs) correspond to which topology. Additionally, that § teaches (¶74) results suggest that the topology of a quadruplex matters in its chaperone function, along with adjacent sequences, but does not disclose what sequence produces each topology or what those adjacent sequences are.
Applicant claims any nucleic acid comprising any specific sequence (wherein the specific sequence comprises one of SEQ ID NOs 1-3) and possessing any particular properties that provide any chaperone activity to any protein-containing compound/tissue/protein. Regarding previous Claim 6 (now incorporated to Claim 1), Applicant claims the specific SEQ ID NOs recited in the claim but has not demonstrated possession of all of those SEQ ID NOs that possess holdase and foldase activity for any protein, and has not disclosed the structure requisite for the holdase and foldase activity. Regarding previous Claim 7 (now incorporated to Claim 1), Applicant has not demonstrated possession of any nucleic acid comprising the claimed SEQ ID NOs possessing holdase or foldase activity or which inhibits aggregation or improves folding of any protein, and has not disclosed the structure required for the holdase and/or foldase activity. Regarding Claim 8, Applicant has not demonstrated possession of any nucleic acid comprising the claimed SEQ ID NOs possessing holdase or foldase activity and which prevents aggregation of any protein by at least 40%. Regarding Claims 11-12, Applicant has not provided specific instructions for altering a specific nucleic acid sequence (wherein the nucleic acid comprises the claimed SEQ ID NOs) to improve chaperone activity or described the pieces of nucleic acid related knowledge that divulge how to alter the nucleic acid sequences. Regarding Claim 13, Applicant has not described what nucleic acids within the claimed SEQ ID NOs correspond with chaperone activity for any protein that corresponds to a specific disease state symptom. Regarding Claim 16, Applicant has not described the nucleic acid structure within the claimed SEQ ID NOs that provides chaperone activity to a plurality of proteins. Although the claims claim the functional characteristic of providing chaperone activity (specifically, limiting protein aggregation or improving protein folding) to any protein, the functional characteristic is not coupled with a known structure.
Although the Specification teaches the examples discussed above, it does not identify a core structure within the claimed SEQ ID NOs necessary for providing chaperone activity to any protein. Among the evidences provided for providing chaperone activity to any protein, no core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for providing chaperone activity to any protein is disclosed in such a way to demonstrate possession of the full invention as claimed at time of filing. There are many proteins so there are many ways of providing chaperone activity to each of them, and the Specification does not teach any defining characteristics of how the claimed SEQ ID NOs provide such chaperone activity or characteristic of how proteins are chaperoned by the claimed SEQ ID NOs.
The specification teaches only a couple members from some of the genera or sub-genera. For example, the SEQ ID NOs shown to provide some chaperone activity. However, the Spec. has disclosed no connection between those specific nucleic acid structures and providing holdase activity vs. providing foldase activity. Furthermore, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genera of any nucleic acid or any compound (or the subgenera) claimed.
Since the disclosure and the prior art fail to describe the common attributes and characteristics concisely identifying members of the proposed genus, and because the claimed genus is highly variant comprising numerous nucleic acids (which comprise the claimed SEQ ID NOs) with varying degrees of binding for any number of proteins, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus claimed.
The MPEP states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163.
Thus one of skill at the time of the invention could not have concluded that Applicant was in possession of the genus of nucleic acids that bind proteins.
While none of these elements is specifically required to demonstrate possession, in combination their absence indicates to one skilled in the art that at the time of filing the inventors lacked possession of an invention a method for providing chaperone activity to any protein containing compound comprising selecting any nucleic acid based on any of its particular properties and specific sequence wherein the nucleic acid comprises a specific sequence comprising at least one of SEQ ID NOs 1-3; selecting based on a nucleic acid’s particular properties that are efficacy of chaperone activity or effect on oligomerization; preventing any protein aggregation (including by 40%) or improving any protein folding; altering the specific sequence of the nucleic acid to improve its chaperone activity for any compound (including wherein altering comprises applying nucleic-acid-related knowledge and screening the nucleic acid); or a method of reducing a disease state symptom using chaperone activity. Claims 1-3, 8, 11-13, and 16 are rejected for failing to demonstrate possession of the claimed invention. Claims 2-3, 8, 11-13, and 16 are rejected because they depend from Claims 1 and/or 11 and do not remedy the issues.
Claims 1-3, 8, 11-13, and 16 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. This is an enablement rejection. These rejections are maintained but updated in response to the claim amendments. All references are of record.
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 specification; (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(a) entails determining what the claims recite and what the claims mean as a whole. Claim 1 recites:
a method for providing chaperone activity to a protein-containing compound, the method comprising:
selecting a nucleic acid based on one or more of the nucleic acid's particular properties and a specific sequence of the nucleic acid; and
applying the nucleic acid to a compound comprising one or more proteins to provide chaperone activity to the compound, wherein the nucleic acid is a G-quadruplex nucleic acid comprising a specific sequence, the specific sequence comprising at least one of: Seq359 (SEQ ID NO:1), Seq536 (SEQ ID NO:2), Seq576 (SEQ ID NO:3), and wherein the chaperone activity comprises at least one of limiting protein aggregation and improving protein folding within the compound.
The broadest reasonable interpretation (BRI) of the claim is that it is a method of providing chaperone activity (specifically the claimed SEQ ID NOs provide chaperone activities of limiting protein aggregation and/or improving protein folding) to any protein containing compound or any protein by selecting a nucleic acid based on its particular properties and sequence (and the sequence has to comprise one of SEQ ID NOs 1-3), and then applying the nucleic acid to the compound. As discussed in §Claim interpretation, “applying” is interpreted as “physically applying” the nucleic acid to the compound.
The nature of the invention is a method of providing chaperone activity (specifically the claimed SEQ ID NOs provide chaperone activities of limiting protein aggregation and/or improving protein folding) to any protein-containing compound to reduce any symptom of any disease. Other issues with the claim are addressed in the 112(a) written description and 112(b) indefiniteness rejections.
A skilled artisan would not be able to use the method as claimed with a reasonable expectation of success based on guidance provided in the specification and art at the time of the filing of the application because of at least the following issues:
Nucleic acid binding between the claimed SEQ ID NOs (wherein the nucleic acid limits protein aggregation and/or improves protein folding) and the full range of claimed targets is not demonstrated.
Nucleic acid specificity between the claimed SEQ ID NOs (wherein the nucleic acid limits protein aggregation and/or improves protein folding) and full range of claimed targets is not demonstrated.
A nucleic acid must make contact with its protein target in order to provide chaperone activity.
The state of the art and prior art, the level of one of ordinary skill, and the level of predictability in the art: A review of the prior art shows (1) aptamers are very specific for their targets (and Applicant hasn’t demonstrated chaperone activity—specifically that the claimed SEQ ID NOs provide the chaperone activities of limiting protein aggregation and/or improving protein folding—for any protein) and (2) in order to provide chaperone activity, a nucleic acid aptamer needs to make physical contact with its protein target.
The art of Zhou (and Rossi. 2016. Aptamers as targeted therapeutics: current potential and challenges. Drug Discov. 16:181-202; “Zhou”) teaches that (§Key Points ¶1) aptamers specifically bind to a molecular target via three-dimensional structures and (§Main text ¶2) aptamers are capable of distinguishing between closely related molecules, such as conformational isomers, targets containing different functional groups or even an amino acid mutation. (emphasis added)
In addition, there are many kinds of proteins. Perez-Iratxeta (et al. 2007. Towards completion of the Earth's proteome. EMBO Rep. 8[12]:1135-1141, “Perez”) teaches (§Abstract) there are approximately 5 million proteins on earth.
Furthermore, the instant claims encompass any protein and the art teaches that protein sequences can vary among individuals. For example, the art of Tang (and Insel. 2005. Genetic variation in G-protein-coupled receptors [GPCR]–consequences for G-protein-coupled receptors as drug targets. Exp. Opin. Therapeut. Targ. 9[6]:1247-1265; “Tang”) teaches that genetic variation alters GPCR structure: (§2.3 GPCR classification ¶3) there are more than 800 GPCRs and that (§3. Genetic polymorphisms ¶1) GPCR loci possess a substantial number of DNA variants, most of which occur within the coding and 5’UTR regions. Tang (§3. Genetic polymorphisms ¶3) teaches that polymorphisms can alter GPCR function and can be responsible for inter-individual differences in ligand binding and signaling.
Antibodies are another kind of protein and can vastly differ. The art of Watson (et al. 2017. The Individual and Population Genetics of Antibody Immunity. Trends Immunol. 38[7]:459-470; “Watson”) teaches (§Abstract) that antibodies produced by immunoglobulin (IG) are the most diverse proteins expressed in humans and that some of the diversity is due to IG-germline variants and (§The Molecular Basis for Antibody Diversity ¶4) individual variation. Watson teaches that (§The Molecular Basis for Antibody Diversity ¶2-4) a naïve antibody repertoire can sample from 10^15 different antibodies and that this impressive baseline diversity can be subsequently augmented when a Bcell encounters and is stimulated by an antigen to undergo somatic hypermutation, resulting in lineages of tens of thousands of clonally derived affinity maturation variants of the initial Ab. ¶4 teaches IG genes are highly variable at the germ-line level, exhibiting extreme allelic polymorphism and gene copy number variation (CNV) between individuals and across populations. Therefore Watson teaches that antibody structures differ based on the naïve repertoire and process of somatic hypermutation—which are variable between individuals and across populations.
The skill level of an artisan is high, but the process of aptamer–target binding is unpredictable because proteins are diverse and comprised of different sequences of amino acids. Furthermore, even the same species of protein can comprise individual amino acid mutations. The teachings of Zhou are clear that aptamers are so precise they can distinguish between targets with a single amino acid mutation. Besides for all that, nucleic acid sequences (i.e., sequences comprising an aptamer) are diverse. Therefore the ability of any aptamer (i.e., a nucleic acid sequence), including the claimed SEQ ID NOs, to bind—let alone provide chaperone activity (wherein the chaperone activities are specifically limiting protein aggregation and/or improving protein folding) to—any protein is highly unpredictable, without presentation of evidence showing otherwise.
Furthermore, regarding G-quadruplexes specifically, the art of Duan (et al. 2025. G-Quadruplex-Protein Interactome at Human Gene Promoters. BioRxiv 02 January 2025. Available online. Accessed on 02 April 2025, “Duan”) teaches that the presence of some proteins on G-quadruplex sequences could be suppressed because the protein may not recognize G4 and therefore occupy only the G4-free regions. The mutual exclusion between the distribution of G4P and that of CEBPZ and DDX20 across the TSS further demonstrated that the latter two proteins were avoided in the presence of G4 (Figure 3C). That indicates that some proteins do not bind G-quadruplexes. Therefore an artisan would conclude that, unless demonstrated otherwise, the ability of any nucleic acid (including the claimed SEQ ID NOs)—even those comprising a G-quadruplex-forming region—to bind—let alone provide chaperone activity (specifically the chaperone activities of limiting protein aggregation and/or improving protein folding) to—any protein is highly unpredictable.
Finally, the art indicates that it would not be possible for a nucleic acid (including the claimed SEQ ID NOs) to provide chaperone activity (specifically the chaperone activities of limiting protein aggregation and/or improving protein folding) for any protein containing compound, even those that are naturally occurring and which comprise tissue or protein, because a chaperone must make physical contact with its protein target, and such contact cannot be made in any circumstance encompassed by the instant claims. Wikipedia teaches that (Chaperone [protein]. Available online at wikipedia.org. Accessed on 01 April 2025, “Wikipedia”) chaperones work by binding their target (see ¶3; §Functions of molecular chaperones ¶2). However, the claims broadly encompass a huge number of “protein-containing compound[s]”, for example amber. The art of McCoy (et al. 2019. Ancient amino acids from fossil feathers in amber. Sci. Rep. 9:6420, “McCoy”) teaches (§Abstract) their findings indicate that the unique fossilization environment inside amber shows potential for the recovery of ancient proteins. McCoy cites (§Introduction ¶2) other papers describing protein inclusion in amber and (§Results and discussion ¶5) other researchers have found that keratin proteins preserve even into the Jurassic27, suggesting that Cretaceous keratin preservation is not at all unexpected or unreasonable. That indicates that the compound amber can contain proteins. McCoy teaches (§Fossil preparation) the amber samples used in their experiments were cut open.
An artisan would readily recognize that the amber samples were cut open because any analysis of amino acids could not be performed on the entire compound containing the sample.
Therefore, without evidence demonstrating otherwise, an artisan would conclude that it would not be possible for any nucleic acid sequence, including the claimed SEQ ID NOs, to provide chaperone activity (specifically the chaperone activities of limiting protein aggregation and/or improving protein folding) to any protein-containing compound by following the steps in the claimed methods.
The amount of direction provided by the specification and the existence of working examples: What is enabled by the working examples does not enable the claimed invention.
The Spec. teaches certain examples:
The examples discuss (¶37-130) only applying nucleic acids to a few purified proteins or to bacteria (which do not possess tissues), not to any protein or any protein-containing compound. Most of the examples in the Spec. describe (¶39-54, Figs 1-5; ¶64-69, Figs 6-8; ¶74-78, Figs 10-12) applying nucleic acids to the protein citrate synthase (CS). Other examples are presented, wherein nucleic acids are applied to (¶54-55 and 64-69, Figs 5-6) the proteins luciferase, L-malate Dehydrogenase (MDH), and L-Lactate dehydrogenase (LDH); (¶71, Fig 9) antibodies to IgG; (¶57-62 and ¶124-128, Figs 15-16) TagRFP675 or wtGFP; and (¶120-124, Figs 13-14) Tau. That is a total of eight proteins out of the (Perez) approximately 5 million proteins on earth. Although the Spec. teaches that (§ starts at ¶53) some of their nucleic acid sequences exhibit general chaperone activity, and that (e.g., ¶41 and ¶127) guanine rich sequences are important for chaperone activity, the Spec. does not demonstrate that any of their nucleic acid sequences exhibits “general chaperone activity”, or that any nucleic acid sequence can exhibit general chaperone activity.
As discussed above, the Spec. discloses two kinds of “chaperone” activity, namely holdase (i.e., what is recited in the claim as limiting protein aggregation) and foldase (i.e., what is recited in the claim as improving protein folding) activities. Most of the examples discuss the effect of a nucleic acid sequence on holdase activity, and only (¶57-62 and ¶125, Fig 16) discuss an effect on foldase activity, and that is only for two proteins that are both fluorescent proteins, wtGFP and TagRFP675.
The Spec. teaches (¶57-62 and ¶124-125) measuring the abundance of TagRFP675 (Fig. 16A-E) and wtGFP (Fig. 16G) fluorescence in the presence of known protein chaperones and some nucleic acid sequences to study their effect on foldase activity (i.e., more fluorescence indicates that the chaperone helped the expressed polypeptide sequence fold properly into a fluorescent protein). Those experiments led to the conclusion that (¶60-62 and ¶127) nucleic acid sequences comprising quadruplexes improve folding. However, even those examples report (¶59, ¶62) that any nucleic acid does not provide foldase activity to any protein—not even those comprising quadruplex sequences: Bulk nucleic acids may have little to no effect on GFP folding or aggregation and the acidic wtGFP was also tested and was less affected by the quadruplex-containing sequences.
Although the Spec. describes that guanine content and G-quadruplexes have something to do with holdase and/or foldase activity, it does not demonstrate that any nucleic acid comprising a G-quadruplex—or the claimed SEQ ID NOs—can provide the claimed functions (limiting protein aggregation and/or improving protein folding) to any protein.
The Spec. teaches (¶59) lack of aptamer effect on GFP folding or aggregation likely stems from electrostatic inhibition, as wtGFP is quite acidic, and would likely be repelled by the negative charge of the nucleic acids’ phosphate backbone but (¶60) TagRFP675 does not have that problem because it is more basic. That indicates that, contrary to Applicant’s claims, it would not be possible for any nucleic acid (or the specific claimed SEQ ID NOs) to provide the claimed chaperone activities—limiting protein aggregation and/or improving protein folding—to any protein because if a nucleic acid cannot contact the protein, it cannot provide chaperone activity.
Even the Spec says (¶55) some single stranded sequences demonstrated little to no activity for all of these proteins and that their data strongly suggest that the holdase activity displayed by quadruplex sequences is general, while also unique to quadruplex-forming sequences.
Additionally, none of the experiments discusses that the protein is within the context of a compound.
In addition, the phrase “limiting protein aggregation” is unclear. It can be interpreted to mean at least (1) reducing formation of aggregates or (2) reducing amount of aggregates. Since Applicant has not shown that their SEQ ID NOs can reduce an amount of aggregates, they have not shown their invention can “limi[t] protein aggregation”.
Altogether the examples don’t enable the invention because the prior art teaches aptamers are very specific for their targets and can detect even a single amino acid difference, because protein targets are so diverse, and there are some protein-containing compounds for which the claimed chaperone activities could not be provided simply by following the method steps because the nucleic acid chaperone could not make contact with the protein. Note that the amber example is a single case but the same concept applies to other protein targets, such as protein inside a bone or inside of an organ. In summary, the guidance present in the specification does not provide any guidance in addressing the enablement issues raised in view of the state of art discussion presented above. An artisan would not be able to use the claimed methods to provide chaperone activity as recited in the claims.
The quantity of experimentation needed to make or use the invention: The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). 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. Given the teachings described above, an artisan of ordinary skill would not be able to use the invention as claimed with a reasonable expectation of success. 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 successfully use the claimed methods of providing chaperone activity (wherein the chaperone activity is limiting protein aggregation and/or improving protein folding) by applying the claimed SEQ ID NOs to any protein-containing compound. Claims 1-3, 8, 11-13, and 16 are rejected for lack of enablement. Claims 2-3, 8, 11-13, and 16 are rejected because they depend from Claims 1 and/or 11 and do not remedy the issues.
Claim 13 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 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. This is an enablement rejection. These rejections are maintained but updated in response to the claim amendments. All references are of record.
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 specification; (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(a) entails determining what the claims recite and what the claims mean as a whole. Claim 13 recites:
a method for providing chaperone activity to a protein-containing compound, the method comprising:
selecting a nucleic acid based on one or more of the nucleic acid's particular properties and a specific sequence of the nucleic acid; and
applying the nucleic acid to a compound comprising one or more proteins to provide chaperone activity to the compound,
wherein the nucleic acid is a G-quadruplex nucleic acid comprising a specific sequence, the specific sequence comprising at least one of: Seq359 (SEQ ID NO:1), Seq536 (SEQ ID NO:2), Seq576 (SEQ ID NO:3), and wherein the chaperone activity comprises at least one of limiting protein aggregation and improving protein folding within the compound,
further comprising reducing a disease state symptom utilizing the chaperone activity.
The broadest reasonable interpretation (BRI) of the claim is that it is a method of providing chaperone activity (specifically, at least one of the chaperone activities of limiting protein aggregation and improving protein folding) to any protein containing compound or any protein by selecting a nucleic acid based on its particular properties and sequence, wherein the nucleic acid is specifically SEQ ID NO 1, 2, or 3; and then applying the nucleic acid to the compound and doing so will reduce any disease state symptom. As discussed in §Claim interpretation, “applying” is interpreted as “physically applying” the nucleic acid to the compound. The nucleic acid recited in the claim and which possesses protein binding capability is also known as an aptamer.
The nature of the invention is a method of providing chaperone activity to a protein-containing compound (specifically, at least one of the chaperone activities of limiting protein aggregation and improving protein folding) to reduce any symptom of any disease. Other issues with the claim are addressed in the 112(a) written description and 112(b) indefiniteness rejections.
A skilled artisan would not be able to use the method as claimed with a reasonable expectation of success based on guidance provided in the specification and art at the time of the filing of the application because of at least the following issues, in addition to those discussed above in the other enablement rejection:
Aptamers are specific for their targets and Applicant hasn’t demonstrated chaperone activity for any protein connected with any disease or disease symptom.
Many proteins are involved in the broad genus of “diseases”.
Applicant has not demonstrated that the claimed nucleic acids (i.e., the specific SEQ ID NOs) can be used to bind any protein and reduce any disease state symptom.
No disease symptom data are provided and it is not a simple matter to deliver aptamers in vivo.
The state of the art and prior art, the level of one of ordinary skill, and the level of predictability in the art: A review of the prior art shows (1) aptamers are very specific for their targets (and Applicant hasn’t demonstrated chaperone activity for any protein connected with any disease or disease symptom), (2) many proteins are involved in the broad spectrum of diseases; (3) any diseases could not be remediated by modulating chaperone activity because some diseases have a cause other than protein aggregation, improper protein folding, or other causes that could be remediated by molecular chaperone activity; (4) the aptamer selection process does not utilize a model of the human blood brain barrier (BBB) so aptamers selected thereby cannot be assumed to cross the BBB.
The art discussed in the other enablement rejection lays out how aptamers are specific for their targets. The art of Wikipedia (“Disease”. Available online at wikipedia.org. Accessed on 02 April 2025, “Wikipedia”) teaches that diseases can be caused by external factors or internal dysfunctions and can include autoimmune diseases.
Regarding autoimmune diseases and specificity of an aptamer for its target, the other enablement rejection discusses the art of Watson which teaches that antibodies can be extremely diverse and vary across individuals. That would indicate to an artisan that autoantibodies, which can be involved in autoimmune diseases, encompass a huge number of diverse and unpredictable proteins. Applicant has not demonstrated that their claimed SEQ ID NOs provide any kind of chaperone activity to those proteins or to a representative number of those proteins.
Regarding the many proteins involved in disease, Abrusan (et al. 2022. Known allosteric proteins have central roles in genetic disease . PLoS Comput. Biol. 18[2]:e1009806, “Abrusan) teaches (§Results-Data summary) they compiled a list of 6170 proteins associated with genetic diseases. Those are just genetic diseases but as discussed in Gonzalez, there are other causes of diseases which involve other proteins. Gonzalez (and Kann 2012. Chapter 4: Protein Interactions and Disease. PLoS Comput Biol. 8[12]:e1002819, “Gonzalez”) teaches (§4. Protein Networks and Disease, entire §) there are many ways proteins can interact to cause a disease. Only some of those are related to protein folding or undesired protein interactions such as aggregation.
Regarding (3) diseases with specific causes, an artisan knows that there are in existence a huge number of diverse diseases including genetic diseases and diseases that are not caused by aberrant protein function. For example, Lung.org (2024. Learn About Coal Worker’s Pneumoconiosis. Accessed on 02 April 2025, “Lung”) teaches that inhaling coal dust causes scarring that leads to coal worker’s pneumoconiosis. There is no evidence that a nucleic acid that binds a protein-containing compound—or the claimed SEQ ID NOs—could reduce a disease state symptom of coal worker’s pneumoconiosis. Similarly, some genetic diseases could not be addressed with the claimed methods because those diseases result from mutations that cause aberrant development or loss of a protein. For example the art of Goodman (2002. Limb malformations and the human HOX genes. Am. J. Med. Genet. 112[3]:256-265, “Goodman”) teaches (§Abstract) Limb malformations may result from chromosomal deletions involving the HOXD and HOXA clusters. Modulating chaperoning of proteins would not affect the disease state symptom of a limb malformation. Furthermore, disorders like factor VIII deficiency could not be addressed with the claimed methods because it can result from protein deficiency. It would not be possible to provide chaperone activity to a protein that is not present. Applicant has not demonstrated that their claimed SEQ ID NOs can provide the sort of chaperone activity claimed for a representative number of disease-associated proteins. Applicant has not demonstrated that providing the sort of chaperone activities claimed could reduce any disease state symptom.
Regarding (