DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Applicant's election of Group II (claims 9-13; drawn to a method of treatment or prevention of neurodegenerative disease comprising administering a recombinant lectin protein) in the reply filed on March 6, 2026 is acknowledged. Claims 1-8 and 14-18 are therefore withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Furthermore, claim 14 was not originally subject to restriction because it was drawn to a non-statutory invention under 35 U.S.C 101; Applicant has presently amended claim 14 (and claims 15-17) to recite “a method of manufacturing a medicament” (i.e., a statutory class of invention). Therefore, Applicant has added a new invention group; claims 14-17 are now placed in this new nonelected invention group. Therefore, claims 1-18 are presently pending; claims 9-11 and 13-17 are presently amended, with claims 1-8 and 14-18 presently withdrawn. Claims 9-13 are presently subject to examination.
Response to Applicant’s Arguments
3. Applicant elected Group II (claims 9-13; drawn to a method of treatment or prevention of neurodegenerative disease comprising administering a recombinant lectin protein) with traverse in the reply filed on March 6, 2026. The claims were restricted on the ground(s) of: the groups of inventions lack unity of invention because the common technical feature linking the groups of inventions—the recombinant lectin protein—does not constitute a special technical feature in light of Peppa et al. The traversal is on the ground(s) of: each of the inventions allegedly shares the common / special technical feature of utilizing neuroprotective effects of the claim-recited lectins in the treatment of neurodegenerative disease. This is not found persuasive that the restriction requirement between Groups I through IV should be withdrawn because:
The invention of Group I (claims 1-8; i.e., a recombinant lectin protein / pharmaceutical composition and intended uses thereof) is a product claim, and the intended uses of the product recited in the preamble does not further limit the structure of the claim-recited protein / composition. See MPEP § 2111.01(I-II).
The invention of new Group III (claims 14-17; i.e., a method of manufacturing a medicament for the treatment or prevention of a neurological disease) is a patentably distinct process for manufacturing a medicament and intended uses of the medicament, wholly unrelated to a method of treatment or prevention of the neurodegenerative disease.
The invention of new Group IV (claim 18 (previously in Group III); i.e., a method of inducing neurite outgrowth in a subject affected by neurodegenerative disease) is a patentably distinct process for inducing neurite outgrowth; neurite outgrowth is a specific structural change to a neuron that may or may not result in the treatment or prevention of the neurodegenerative disease (i.e., prophylactic effect or reduction of the symptomology of the neurodegenerative disease), whereas a method of treatment or prevention requires prophylactic effect or reduction of the symptomology of the neurodegenerative disease and does not require the induction of neurite outgrowth.
Therefore, the inventions of Groups I-IV do not share a common technical feature of: utilizing the neuroprotective effects of the claim-recited lectins in the treatment of neurodegenerative disease and/or in compositions for the treatment of neurodegenerative disease.
Since the inventions of Groups I-IV are patentably distinct, the requirement is still deemed proper and is therefore made FINAL.
Information Disclosure Statement
3. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Objection to the Specification
4. The instant specification is objected to for the following reasons:
a. There are trademarks in this application that do not meet the requirements.
The use of the term (e.g., ATCC at pg. 33, line 12), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
There are references in this specification that should be placed on an information disclosure statement if application would like them considered.
Objections to the Claims
5. Claims 12 and 13 are objected to because of the following informalities:
a. Claim 12 recites “wherein the neurodegenerative [disease] is selected from [… .]” “Neurodegenerative” is an adjective and requires the subsequent noun “disease” to be grammatically proper.
b. Claim 13 recites “administering recombinant lectin protein” rather than “administering the recombinant lectin protein.” The lack of antecedent basis makes it unclear if “recombinant lectin protein” refers to the recombinant lectin protein of claim 9, from which claim the claim depends, or any recombinant lectin protein. Appropriate correction is required.
Claim Rejections - 35 USC § 112
6. 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
7. Claims 9-13 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 claims contain 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that:
"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." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
No written description for the breath of the claims (“neurodegenerative disease”):
Claim 9 is drawn to a method of treatment or prevention of neurodegenerative disease in a subject, the method comprising administering to the subject an effective amount of a recombinant lectin protein selected from SEQ ID NO. 1, SEQ ID NO. 2 or SEQ ID NO. 3 or a pharmaceutical composition of the recombinant lectin protein and a pharmaceutically acceptable excipient.
Claim 10 is drawn to the method of treatment or prevention of neurodegenerative disease in a subject as claimed in claim 9, wherein the amino acid sequence has at least 75%, 80%, 90%, 95%, 96%, 97%, 98% or 99% homology to SEQ ID NO.4.
Claim 11 is drawn to the method of treatment or prevention of neurodegenerative disease in a subject as claimed in claim 9, wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, dementia, cognitive disorder, symptoms related to dementia, Huntington's disease, prion diseases such as Creutzfeld-Jacob disease, Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, cerebral degenerative diseases, spinal and bulbar muscular atrophy (SBMA), Ataxia, Pick's disease, primary progressive aphasia, multiple system atrophy, pantothenate kinase- associated neurodegeneration (PANK), spinal degenerative disease/motor neuron degenerative diseases, hippocampal sclerosis, corticobasal degeneration, Batten disease motor neuron disease like Amyotrophic lateral sclerosis (ALS, also termed Lou Gehrig's disease), primary lateral sclerosis (PLS), progressive bulbar palsy (PBP) a variant of ALS, Pseudo bulbar palsy and Hereditary spastic paraplegia.
Claim 12 is drawn to the method of the treatment or prevention of neurodegenerative disease in a subject as claimed in claim 11, wherein the neurodegenerative is selected from Alzheimer's disease, Parkinson's disease, dementia, cognitive disorder and symptoms related to dementia.
Claim 13 is drawn to the method of treatment of neurodegenerative disease as claimed in claim 9 comprising administering recombinant lectin protein at a dose of 0.01 mg/kg to 1000 mg/kg.
The claims therefore broadly encompass methods of treatment or prevention of the genus “neurodegenerative disease” with the claim-recited lectins. The claimed lectin must possess specific functions, including treating or preventing “neurodegenerative disease” in general. However, there is no structure recited in the claims that would correlate with this function. The specification only sets forth the claim-recited lectins as potentially being effective for treating or preventing AZ and dementia, but these two species of neurological diseases are not sufficiently representative of the broad genus of “neurodegenerative disease” instantly claimed.
The specification discloses: assessments of undifferentiated SH-SY5Y cell viability when exposed to MPP+ with and without pretreatment with the recombinant lectin of SEQ ID NO: 1 (Examples 1-2); assessments of differentiated PC-12 cell neurite outgrowth when exposed to MPP+ with and without treatment with the recombinant lectin (Example 3); measurements of biomarkers in undifferentiated SH-SY5Y cells when exposed to MPP+ or SCO with and without pretreatment with the recombinant lectin of SEQ ID NO: 1 (Example 4); and in vivo behavioral tests and histopathology of mice exposed to SCO with and without pretreatment with the recombinant lectin of SEQ ID NO: 1 (Example 5).
The claims encompass that any species of the genus “neurodegenerative disease” may be treated or prevented with the claim-recited lectins, however the genus “neurodegenerative disease” is highly variable: for example, AZ / dementia is primarily a memory disorder caused by cholinergic disfunction, whereas PD is primarily a movement disorder caused by dopaminergic dysfunction. The specification’s examples only disclose that the lectin may treat or prevent AZ / dementia, yet the claims encompass the treatment or prevention of any neurodegenerative disease. To address this issue, a brief assessment of the state of the art of neurodegenerative disease treatments and models is provided below, which shows it is highly unpredictable if a therapeutic that shows promise to beneficially treat one neurodegenerative disease (i.e., AZ) may also beneficially treat another neurodegenerative disease (e.g., PD).
The specification only discloses in vivo treatment of a scopolamine (SCO) model with the claim-recited lectin. The art has recognized SCO—a cholinergic antagonist—as the standard for modeling hallmark cholinergic disfunction of claim-recited AZ / dementia, but SCO does not model other claim-recited neurodegenerative diseases (e.g., dopaminergic disfunction in PD). Therefore, the in vivo SCO model only provides written description for treating AZ / dementia.
Furthermore, no singular in vivo model reads on the diversity of neurodegenerative diseases encompassed by the claims because neurodegenerative diseases have distinct etiologies (e.g., PD relates to dopaminergic system disfunction, whereas AZ relates to cholinergic system disfunction). To address this issue, a brief assessment of the state of the art of the disclosed SCO model is provided below, which shows the SCO model is uniquely and specifically useful for modeling AZ / dementia, and therefore it is highly unpredictable if results obtained with the SCO model has relevance to any of the claim-recited neurodegenerative diseases other than AZ / dementia.
Szala-Rycaj et al. ("Neuroprotective potential of phytocompounds in the treatment of dementia: the state of knowledge from the scopolamine-induced animal model of Alzheimer’s disease." Current Issues in Molecular Biology 47.8 (2025): 635) is a review of the neuroprotective potential of select natural substance in the commonly performed in vivo SCO-induced animal model of AZ disease. Szala-Rycaj et al. at abstract. Szala-Rycaj et al. also characterizes AZ as a type of dementia. Id. FIG. 1 of Szala-Rycaj et al. shows that SCO results in cholinergic disfunction, relevant to AZ. Szala-Rycaj et al. teaches that: “SCO is widely used in basic in vivo research studies to induce an impairment in cognitive functions and memory that is very similar to AD in terms of the main characteristics, which are cholinergic dysfunction and the accumulation of amyloid-β plates. Additionally, SCO induces changes such as impaired antioxidant defense systems, increased oxidative stress, mitochondrial dysfunction, apoptosis, and neuroinflammation, which mimic those that occur in AD patients. Although the SCO model has some limitations, it is one of the best and easiest in vivo models for use in research on AD.” Szala-Rycaj et al. at section 1.3. Szala-Rycaj et al. further teaches that: SCO easily crosses the blood–brain barrier (BBB) and acts in the CNS, leading to the appearance of problems with spatial memory and electrophysiological changes that resemble the symptoms of AD. Additionally, SCO advances the cleavage pathway of alternative amyloid precursors, which causes the development of amyloid β plaques.” Szala-Rycaj et al. at section 3; see also FIG. 3. Importantly, Szala-Rycaj et al. also teaches that: SCO causes functional problems but does not cause nerve cell destruction or progressive neurodegeneration, so it is not a good model for chronic neurodegenerative diseases,” and that “the [SCO] model should be viewed as an adjunct to more complex models of neurodegenerative diseases, not as a replacement for them.” Szala-Rycaj et al. at section 5. Therefore Szala-Rycaj et al. teaches that the SCO model is a recognized model for AZ / dementia, but not neurodegenerative disease in general.
Sanfeliu,et al. ("New insights in animal models of neurotoxicity-induced neurodegeneration." Frontiers in neuroscience 17 (2024): 1248727) is a review of animal models for neurotoxicity-induced neurodegeneration. Sanfeliu,et al at title. FIG. 1 of Sanfeliu et al. shows that PD models do not include the SCO model (but does include the MPTP/MPP+ model), whereas FIG. 2 shows that AD models include the SCO model. Sanfeliu,et al. specifically teaches that: “Cholinergic neurodegeneration is mainly modelled with the toxin scopolamine, which is a useful rodent model for the screening of protective drugs against cognitive decline and AD.” Sanfeliu,et al. at abstract. In contrast, Sanfeliu,et al. teaches regarding PD: “In the CNS, there exist four main dopaminergic systems: nigrostriatal and ventral tegmental, mesocortical, mesolimbic, and tuberoinfundibular area. The progressive, lengthy, relatively selective, extensive, and irreversible loss of dopaminergic neurons in the substantia nigra (SN) pars compacta and their projections in the corpus striatum (caudate nucleus and putamen) constitute the main pathological manifestation of the neurodegenerative disorder present in PD. A second hallmark of PD is the presence in the nigrostriatal dopaminergic neurons of characteristic cytoplasmic inclusions known as Lewy bodies, which contain fibrils of misfolded α-synuclein protein.” Sanfeliu,et al. at section 2.1.
Therefore, the combination of Szala-Rycaj et al. and Sanfeliu,et al. teaches that AZ and PD have distinct etiologies (i.e., AZ being cholinergic and PD being dopaminergic), with the SCO model specifically reading on AZ / dementia and not PD. It is therefore highly unpredictable how results obtained with an AZ / dementia model would translate to the treatment of other neurodegenerative diseases, since Sanfeliu,et al. shows that distinct animal models were specifically developed for the purpose of testing therapeutics for the other neurodegenerative diseases, e.g., PD.
The specification’s disclosure of in vitro effects using undifferentiated SH-S75Y cells is also insufficient to provide written description for the treatment / prevention of “neurodegenerative diseases.” The art has recognized the need to differentiate SH-S75Y cells to model neurogenerative disease (e.g., PD) because undifferentiated SH-S75Y cells resemble cancer cells, not the neurons implicated in neurodegenerative diseases.
The specification only discloses in vitro effects of the claim-recited lectin using two in vitro models: a thorough disclosure of SCO and MPP+ effects in SH-S75Y cells with the claim-recited lectin; and a singular assessment of neurite outgrowth in PC12 cells with the lectin disclosed at Table 5 (addressed below). However, although SH-S75Y cells and MPP+ are recognized by the art to have probative value as to PD, the instant disclosure lacks PD probative value because the SH-S75Y cells were not differentiated SH-S75Y cells and therefore were more like neuroblastoma / cancer cells. To address this issue, a brief assessment of the state of the art of SH-S75Y cells is made herein, which shows that differentiating the SH-S75Y cells is necessary to model PD, let alone a “neurodegenerative disease” in general. Since Applicant never differentiated the SH-S75Y cells, the instantly disclosed results using the SH-S75Y cells do not cure the above-discussed deficiencies with the in vivo SCO model to demonstrate the claim-recited lectin has preventative or therapeutic effect for any neurodegenerative diseases other than AZ / dementia.
Pandey et al. ("The SH-SY5Y cell line: a valuable tool for Parkinson’s disease drug discovery." Expert Opinion on Drug Discovery 19.3 (2024): 303-316) is a review of use of SH-S75Y cells in vitro for PD drug discovery. Pandey et al. at title. Pandey et al. teaches that: “Immortalized human neuroblastoma SH-SY5Y cell lines offer a human-origin and ethically sound alternative to animal models for studying PD mechanisms. Their differentiation into dopaminergic neurons allows researchers to replicate PD-related cellular changes, including α-synuclein aggregation and mitochondrial dysfunction.” Pandey et al. at introduction. Furthermore: “SH-SY5Y cells can be induced to differentiate into a more mature neuronal phenotype. By differentiating SH-SY5Y cells into dopaminergic-like neurons, a more specific model for studying PD-related processes can be created for research purposes. Thereby, it serves as a valuable tool for investigating PD-related cellular processes and has contributed significantly to the understanding of the disease’s mechanisms and the testing of potential therapeutic interventions.” Pandey et al. at section 3. And to the extent SH-SY5Y cells can be used to model AZ: “The SH-SY5Y cell line serves as a valuable tool in studying TAU biology and neurodegenerative diseases like Alzheimer’s due to its ability to differentiate into neuron-like cells resembling human neurons.” Pandey et al. at section 3.1. Therefore Pandey et al. teaches that the SH-SY5Y cell line is a valuable tool for specific neurodegenerative diseases—when the cell line is differentiated.
Artimagnella et al. ("Dopaminergic Identity of SH-SY5Y Cells Across Differentiation Protocols in Parkinson’s Disease Research: A Systematic Review." International Journal of Molecular Sciences 27.8 (2026): 3355) is a review of SH-SY5Y cell differentiation protocols. Artimagnella et al. at title. Artimagnella et al. teaches: “The use of SH-SY5Y cells in PD research critically relies on their ability to differentiate into a mature, post-mitotic, dopaminergic (DAergic) neuronal phenotype. However, SH-SY5Y cells are inherently heterogeneous since they are firstly catecholaminergic cells and may express diverse phenotypic markers besides the DAergic ones. These properties seem to be determined by the differentiation protocol that is employed, thus meaning it is crucial to obtain proper cell types.” Artimagnella et al. at abstract. Artimagnella et al. further teaches that: “neurodegeneration affects distinct neuronal populations depending on the pathology, for instance, DAergic neurons in PD and cholinergic neurons in AD. Consequently, the selection of an appropriate differentiation protocol is critical to obtaining the desired cellular phenotype,” and most importantly that “it is noteworthy that many studies choose to bypass the differentiation process entirely to avoid introducing additional experimental variables; however, this approach inherently limits the physiological relevance and investigative power of the model.” Artimagnella et al. at discussion. That is the case here—Applicant has bypassed using any differentiation protocol, and therefore limited the physiological relevance and power of the results disclosed.
The necessity of differentiating the SH-SY5Y cells is further corroborated by Ioghen, et al. ("SH-SY5Y cell line in vitro models for Parkinson disease research—old practice for new trends." Journal of integrative neuroscience 22.1 (2023): 20), a review of the use of SH-SY5Y cells to model PD. Ioghen, et al. at abstract. Ioghen, et al. teaches that: “the use of the SH-SY5Y cell line represents a basic but consistent first step in experiments related to PD, but which must be followed by the confirmation of the results through more complex in vitro and in vivo experimental models.” Id. Ioghen, et al. further teaches that: “The induction of differentiation of the SH-SY5Y cell line into dopaminergic neurons is usually the first step for developing in vitro experimental designs to study PD. The morphological aspects of the neurons and the low proliferation rate makes the differentiated cells resemble the primary mesencephalic dopaminergic neurons, while the undifferentiated cells are much closer to a cancerous type of cell, related to their neuroblastoma origin.” Ioghen, et al. at section 3. Therefore, not only were SH-SY5Y cells disclosed in the specification closer to cancerous cells than dopaminergic cells, but Applicant also did not no follow through with a PD in vivo model that may provide some confidence that the claim-recited lectin may treat PD, let alone neurodegenerative diseases other than AZ / dementia.
Last, the specification’s disclosure of an in vitro MPP+ PC12 neurite outgrowth assay does not cure the written description deficiencies discussed above; Applicant does not have possession of treating or preventing genus “neurodegenerative disease.”
The specification therefore only discloses in vivo effects of the claim-recited lectin using an SCO AZ / dementia model; and in vitro effects using two in vitro models: a thorough disclosure of SCO and MPP+ effects in undifferentiated SH-S75Y cells with the claim-recited lectin; and a singular assessment of MPP+ neurite outgrowth effects in PC12 cells with the claim-recited lectin disclosed at Table 5. However, a “neurite outgrowth” assay in PC-12 cells is insufficient to cure the deficiencies laid out above because it is unpredictable how results obtained in vivo with one SCO AZ / dementia animal model will translate to the treatment of “neurodegenerative diseases” in general, let alone how a PC-12 cell “neurite outgrowth” assay using MPP+ cures this deficiency. To address this issue, a brief assessment of the state of the art of translating in vitro results to preventing or treating neurodegenerative diseases is presented herein, showing that in vitro results are just a starting point for demonstrating therapeutic effect, and that a majority of “promising” candidate drugs fail to actually treat the targeted neurodegenerative disease. Therefore, the MPP+ PC-12 “neurite outgrowth” results in view of the SCO AZ / dementia animal model results does not demonstrate the treatment or prevention of genus “neurodegenerative disease.”
El Elhaj et al. ("Exploring Neurodegenerative Diseases: Bridging the Gap between in vitro and in vivo Models." Current Pharmaceutical Design (2025)) is a review discussing the strengths and weaknesses of in vitro vs in vivo models for neurodegenerative disease translational research. El Elhaj et al. at conclusion. El Elhaj et al. teaches: “In vitro models provide cost and complexity reduction, environment control, and high-throughput screening of potential therapeutic agents compared to in vivo models. Nevertheless, they possess constraints, including the absence of intricate interactions that transpire in the entire organism and the inability to reproduce the disease progression completely.” El Elhaj et al. at abstract. Therefore, in vitro models are a starting point that may suggest a particular therapeutic holds promise to prevent or treat a neurodegenerative disease, but the in vitro models still require corroboration from in vivo models.
Kim et al. ("Alzheimer’s disease: key insights from two decades of clinical trial failures." Journal of Alzheimer’s Disease 87.1 (2022): 83-100) is review of two decades of clinical trials results for AZ therapeutics. Kim et al. at title. Kim et al. teaches: “The two recent reported phase III successes of aducanumab and oligomannate are very encouraging; however, we are awaiting real-world validation of their effectiveness. These two successes against the 98 failures gives a 2.0% phase II and III success rate since 2003, when the previous novel compound was approved.” Kim et al. at abstract. Therefore, Kim et al. teaches it is very unpredictable which promising therapeutics actually prevent or treat a disease in vivo. In the instant case, disclosure of a single PC-12 “neurite outgrowth” assay and results obtained from undifferentiated SH-S75Y cells does not cure the deficiency that the specification only discloses in vivo results that read on AZ / dementia because it is highly unpredictable how the in vitro results will translate into treating or preventing all the “neurodegenerative diseases” encompassed by the claims.
No written description for “prevention” of neurodegenerative disease.
The claims recite a method of treatment or prevention of neurodegenerative disease. Although the examples may demonstrate some prophylactic effects of the claim-recited lectins for AZ / dementia (e.g., the in vivo model of Example 5 pre-treats the mice with the lectin for 14 days before administering the SCO AZ / dementia model), this does not rise to the level of showing “prevention” of neurodegenerative disease because the mice still ultimately developed the (SCO AZ / dementia model) neurodegenerative disease.
The Merriam-Webster dictionary defines the term “prevent” as: “to keep from happening or existing.” It gives the example of preventing a war, which means no war occurred. (www.merriam-webster.com/dictionary/prevent)
The Merriam-Webster dictionary defines the term “treat” as: “to care for or deal with medically or surgically.” It gives the example of treating a disease. (www.merriam-webster.com/dictionary/treat)
Example 5 shows e.g., that mice pre-treated with the claim-recited lectin had an intermediate Mean Transfer Latency Time (MTLT) in the Passive Avoidance Test compared to negative and positive SCO controls. See instant Table 10 (negative controls had a MTLT of 135.7 seconds; positive controls had a MTLT of 56.93 seconds; mice pre-treated with the claim-recited lectin had intermediate MTLTs of 75.81-85.26 seconds). The mice therefore still developed symptoms of the SCO AZ / dementia neurodegenerative disease, albeit to a lesser extent than the positive SCO control. Accordingly, “prevention” of neurodegenerative disease was not demonstrated in the instant specification; “treatment” was demonstrated because the SCO model was dealt with medically (i.e., by administering the claim-recited lectin), and a reduced form (i.e., not a prevention) of the SCO neurodegenerative disease resulted. It is therefore highly unpredictable if the claim-recited lectins can “prevent” the occurrence of any of the claim-recited neurodegenerative diseases since it did not prevent development of AZ / dementia symptoms in the in vivo SCO AZ / dementia model shown in Example 5.
No written description for fragments and variants of the recombinant lectin of SEQ ID NO:4 encompassed by claim 10.
Claim 10 recites that the recombinant lectin protein amino acid sequence may have “at least 75%, 80%, 90%, 95%, 96%, 97%, 98% or 99% homology to SEQ ID NO.4.” This claim therefore encompasses hundreds of fragments and variants of SEQ ID NO: 4 having at least 75% homology to SEQ ID NO: 4. The specification indicates SEQ ID NO: 4 is WT S. rolfsii lectin at page 16 line 18. The specification indicates the S. rolfsii lectin has affinity for TF and Tn antigen at page 4, line 11. The specification does not disclose which fragments / variants encompassed by “at least 75%” homology may retain these functional properties or still be considered a S. rolfsii lectin.
In contrast, the specification only discloses the use of SEQ ID NO: 1, which varies from 141 AA-long SEQ ID NO: 4 by substitutions: N14D, E113Q, and E123Q.
The claims recite functional language of the recombinant lectin, such as prevents or treats neurodegenerative disease, however a definition by function does not suffice to define the genus because it is only an indication of what the recombinant lectin does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of recombinant lectin is highly variable (i.e., each recombinant lectin would necessarily have a unique structure), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed recombinant lectins have no correlation between their structure and function. To address this issue, a brief assessment of the state of the art of the consequences of fragmenting proteins or peptides is provided below, which demonstrates the general principle that it is highly unpredictable what biological activity fragments of the recombinant lectin protein encompassed by claim 10 will have, let alone for treating or preventing the genus “neurodegenerative disease.”
Souza‐Silva et al. ("Peptide fragments of bradykinin show unexpected biological activity not mediated by B1 or B2 receptors." British Journal of Pharmacology 179.12 (2022): 3061-3077) teaches regarding fragments of the 9 amino acid Bradykinin sequence: “BK-(1–7) and BK-(1–5) are produced in vivo from BK-(1–9). Both peptides induced NO production in all cell types tested. However, unlike BK-(1–9), NO production elicited by BK-(1–7) or BK-(1–5) was not inhibited by B1 or B2 receptor antagonists.” Souza‐Silva et al. at abstract. Therefore, it was unpredictable that fragments of this 9 amino acid sequence would have substantially different biological activity compared to the full-length amino acid sequence.
In contrast, Zablocki et al. ("Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor." Journal of medicinal chemistry 36.13 (1993): 1811-1819) teaches regarding a fragment of the 4 amino acid RGDF sequence that surprisingly: “[p]reviously, we had shown that the inherent inhibitory potency of Arg-Gly-Asp-Phe [RGDF] for disrupting the fibrinogen-GP Ilb-IIIa interaction can be enhanced 15-fold by removing the Arg-NH2 and the Arg-Gly amide bond to obtain 8-guanidinooctanoyl-Asp-Phe[GOA-Asp Phe]” Zablocki et al. at introduction. In other words, the fragment of the 4 amino acid sequence showed a large increase in inhibitory activity compared to the full-length tetrapeptide.
The above juxtaposition of a fragmenting a short amino acid sequence resulting in substantially different biological activity as illustrated by Souza‐Silva et al. compared to fragmenting a different short amino acid sequence resulting in a large increase in (inhibitory) activity illustrated by Zablocki et al. shows it is very unpredictable what effects will be obtained with all the possible fragments and variants of SEQ ID NO: 4 encompassed by claim 10. Therefore, without performing the required experiments it is wholly unpredictable which fragments and variants having at least 75% homology to SEQ ID NO: 4 may retain biological activity, let alone biological activity that prevents or treats “neurodegenerative diseases” in general.
Neither the art nor the specification provides a sufficient representative number of (i) neurodegenerative diseases prevented and/or treated with the recombinant lectin; or (ii) variants / fragments of the recombinant lectin of SEQ ID NO: 4 that may retain functionality; to meet the written description requirement for instant claims directed to the prevention and treatment of “neurodegenerative disease” in general and/or variants and fragments of SEQ ID NO: 4.
It is therefore unknown how the genus of “neurodegenerative disease” would be prevented or treated by the genus of recombinant lectin fragments / variants instantly claimed. Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genera of recombinant lectins and “neurodegenerative disease” encompassed by the claims. Given all of the above, Applicant does not have written description preventing or treating “neurodegenerative disease” with the claim-recited recombinant lectins.
The cited reference therefore demonstrate that Applicant is not in possession of: preventing or treating “neurodegenerative disease” with the claim-recited lectins; Applicant is in possession of treating AZ and dementia with a recombinant lectin selected from SEQ ID NO: 1-4.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the 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. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Enablement
8. Claims 9-13 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 preventing or treating AZ and dementia with the recombinant lectin consisting of SEQ ID NO: 1-4, does not reasonably provide enablement for preventing or treating other neurodegenerative diseases with other recombinant lectin proteins. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). 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 (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(2) The breadth of the claims:
The claims are drawn to a method of treatment or prevention of “neurodegenerative disease” with a recombinant lectin protein selected from SEQ ID NOs: 1-4. The dependent claims further recite a laundry list of neurodegenerative diseases; that the recombinant lectin can have at least 75% homology to SEQ ID NO: 4; and dosages of the recombinant lectin.
The claims are therefore broad and encompass preventing or treating any neurodegenerative disease with recombinant lectin proteins having SEQ ID NOs: 1-4, or recombinant lectin proteins having at least 75% homology to SEQ ID NO: 4, which includes fragments and variants of SEQ ID NO: 4.
(5) The predictability or unpredictability of the art:
The state of the art indicates it is very unpredictable (i) how well members of the genus “neurodegenerative disease” may be prevented or treated by a given therapeutic, and (ii) how interchangeable members of the recombinant lectin genus: “at least 75% homology to SEQ ID NO: 4” may be to prevent or treat the “neurodegenerative disease.”
It is unpredictable what neurodegenerative diseases scopolamine (SCO) models other than AZ / dementia.
The specification only discloses in vivo effects of the claim-recited lectin using one model: SCO treatment of mice. However, no singular in vivo model reads on all the neurodegenerative diseases encompassed by the claims. To address this issue, a brief assessment of the state of the art of the disclosed SCO model is provided below, which shows the SCO model is specifically useful for modeling AZ / dementia, and therefore it is highly unpredictable if results obtained with the SCO model reads on any neurodegenerative disease other than AZ / dementia.
Szala-Rycaj et al. ("Neuroprotective potential of phytocompounds in the treatment of dementia: the state of knowledge from the scopolamine-induced animal model of Alzheimer’s disease." Current Issues in Molecular Biology 47.8 (2025): 635) is a review of the neuroprotective potential of select natural substance in the commonly performed in vivo SCO-induced animal model of AZ disease. Szala-Rycaj et al. at abstract. Szala-Rycaj et al. also characterizes AZ as a type of dementia. Id. FIG. 1 of Szala-Rycaj et al. shows that SCO results in cholinergic disfunction, relevant to AZ. Szala-Rycaj et al. teaches that: “SCO is widely used in basic in vivo research studies to induce an impairment in cognitive functions and memory that is very similar to AD in terms of the main characteristics, which are cholinergic dysfunction and the accumulation of amyloid-β plates. Additionally, SCO induces changes such as impaired antioxidant defense systems, increased oxidative stress, mitochondrial dysfunction, apoptosis, and neuroinflammation, which mimic those that occur in AD patients. Although the SCO model has some limitations, it is one of the best and easiest in vivo models for use in research on AD.” Szala-Rycaj et al. at section 1.3. Szala-Rycaj et al. further teaches that: “SCO a non-selective muscarinic receptor antagonist that causes cholinergic dysfunction by disrupting the regulation of AChE, one of the most important neurotransmitters in memory processing. Due its high lipophilicity, SCO easily crosses the blood–brain barrier (BBB) and acts in the CNS, leading to the appearance of problems with spatial memory and electrophysiological changes that resemble the symptoms of AD. Additionally, SCO advances the cleavage pathway of alternative amyloid precursors, which causes the development of amyloid β plaques.” Szala-Rycaj et al. at section 3; see also FIG. 3. Importantly, Szala-Rycaj et al. also teaches that: “Despite the many benefits of using this [SCO] model for in vivo studies, there are also drawbacks and problems, including the lack of structural neurodegenerative changes. SCO causes functional problems but does not cause nerve cell destruction or progressive neurodegeneration, so it is not a good model for chronic neurodegenerative diseases,” and that “the [SCO] model should be viewed as an adjunct to more complex models of neurodegenerative diseases, not as a replacement for them.” Szala-Rycaj et al. at section 5. Therefore Szala-Rycaj et al. teaches that the SCO model is a recognized model for AZ / dementia, but not neurodegenerative disease in general.
Sanfeliu,et al. ("New insights in animal models of neurotoxicity-induced neurodegeneration." Frontiers in neuroscience 17 (2024): 1248727) is a review of animal models of neurotoxicity-induced neurodegeneration. Sanfeliu,et al at title. FIG. 1 of Sanfeliu et al. shows that PD models do not include the SCO model (but does include the MPTP/MPP+ model), whereas FIG. 2 shows that AD models include the SCO model. Sanfeliu,et al. specifically teaches that: “Cholinergic neurodegeneration is mainly modelled with the toxin scopolamine, which is a useful rodent model for the screening of protective drugs against cognitive decline and AD.” Sanfeliu,et al. at abstract. In contrast, Sanfeliu,et al. teaches regarding PD: “In the CNS, there exist four main dopaminergic systems: nigrostriatal and ventral tegmental, mesocortical, mesolimbic, and tuberoinfundibular area. The progressive, lengthy, relatively selective, extensive, and irreversible loss of dopaminergic neurons in the substantia nigra (SN) pars compacta and their projections in the corpus striatum (caudate nucleus and putamen) constitute the main pathological manifestation of the neurodegenerative disorder present in PD. A second hallmark of PD is the presence in the nigrostriatal dopaminergic neurons of characteristic cytoplasmic inclusions known as Lewy bodies, which contain fibrils of misfolded α-synuclein protein. The clinical features of the striatal loss of dopamine in PD are resting tremor, postural and gait dysfunction, bradykinesia, muscular rigidity, etc.” Sanfeliu,et al. at section 2.1. Therefore, the combination of Szala-Rycaj et al. and Sanfeliu,et al. teaches that AZ and PD have distinct etiologies (i.e., AZ being cholinergic and PD being dopaminergic), with the SCO model specifically reading on AZ / dementia and not PD. It is therefore highly unpredictable how results obtained with an AZ / dementia model would translate to the treatment of other neurodegenerative diseases, since Sanfeliu,et al. shows that distinct animal models were specifically developed for the purpose of testing therapeutics for the other neurodegenerative diseases, e.g., PD.
It is unpredictable what neurodegenerative diseases undifferentiated SH-S75Y cells model.
The specification only discloses in vitro effects of the claim-recited lectin using two in vitro models: a thorough disclosure of SCO and MPP+ effects in SH-S75Y cells with the claim-recited lectin; and a singular assessment of neurite outgrowth in PC12 cells with the lectin at Table 5 (addressed below). However, although SH-S75Y cells and MPP+ are recognized by the art to have probative value as to PD, the instant disclosure lacks PD probative value because the SH-S75Y cells were not differentiated SH-S75Y cells. To address this issue, a brief assessment of the state of the art of SH-S75Y cells is made herein, which shows that differentiating the SH-S75Y cells is necessary to model PD, let alone a “neurodegenerative disease” in general. Since Applicant never differentiated the SH-S75Y cells, the instantly disclosed results using the SH-S75Y cells do not cure the above-discussed deficiencies with the in vivo SCO model to demonstrate the claim-recited lectin has preventative or therapeutic effect for any neurodegenerative diseases other than AZ / dementia.
Pandey et al. ("The SH-SY5Y cell line: a valuable tool for Parkinson’s disease drug discovery." Expert Opinion on Drug Discovery 19.3 (2024): 303-316) is a review of use of SH-S75Y cells in vitro for PD drug discovery. Pandey et al. at title. Pandey et al. teaches that: “Immortalized human neuroblastoma SH-SY5Y cell lines offer a human-origin and ethically sound alternative to animal models for studying PD mechanisms. Their differentiation into dopaminergic neurons allows researchers to replicate PD-related cellular changes, including α-synuclein aggregation and mitochondrial dysfunction.” Pandey et al. at introduction. Furthermore: “SH-SY5Y cells can be induced differentiate into a more mature neuronal phenotype. By differentiating SH-SY5Y cells into dopaminergic-like neurons, a more specific model for studying PD-related processes can be created for research purposes. Thereby, it serves as a valuable tool for investigating PD-related cellular processes and has contributed significantly to the understanding of the disease’s mechanisms and the testing of potential therapeutic interventions.” Pandey et al. at section 3. And to the extent SH-SY5Y cells can be used to model AZ: “The SH-SY5Y cell line serves as a valuable tool in studying TAU biology and neurodegenerative diseases like Alzheimer’s due to its ability to differentiate into neuron-like cells resembling human neurons.” Pandey et al. at section 3.1. Therefore Pandey et al. teaches that the SH-SY5Y cell line is a valuable tool for specific neurodegenerative diseases—when the cell line is differentiated.
Artimagnella et al. ("Dopaminergic Identity of SH-SY5Y Cells Across Differentiation Protocols in Parkinson’s Disease Research: A Systematic Review." International Journal of Molecular Sciences 27.8 (2026): 3355) is a review of SH-SY5Y cell differentiation protocols. Artimagnella et al. at title. Artimagnella et al. teaches: “The use of SH-SY5Y cells in PD research critically relies on their ability to differentiate into a mature, post-mitotic, dopaminergic (DAergic) neuronal phenotype. However, SH-SY5Y cells are inherently heterogeneous since they are firstly catecholaminergic cells and may express diverse phenotypic markers besides the DAergic ones. These properties seem to be determined by the differentiation protocol that is employed, thus meaning it is crucial to obtain proper cell types.” Artimagnella et al. at abstract. Artimagnella et al. further teaches that: “neurodegeneration affects distinct neuronal populations depending on the pathology, for instance, DAergic neurons in PD and cholinergic neurons in AD. Consequently, the selection of an appropriate differentiation protocol is critical to obtaining the desired cellular phenotype,” and most importantly that “it is noteworthy that many studies choose to bypass the differentiation process entirely to avoid introducing additional experimental variables; however, this approach inherently limits the physiological relevance and investigative power of the model.” Artimagnella et al. at discussion. That is the case here—Applicant has bypassed using any differentiation protocol, and therefore limited the physiological relevance and power of the results disclosed.
The necessity of differentiating the SH-SY5Y cells is further corroborated by Ioghen, et al. ("SH-SY5Y cell line in vitro models for Parkinson disease research—old practice for new trends." Journal of integrative neuroscience 22.1 (2023): 20), a review of the use of SH-SY5Y cells to model PD. Ioghen, et al. at abstract. Ioghen, et al. teaches that: “the use of the SH-SY5Y cell line represents a basic but consistent first step in experiments related to PD, but which must be followed by the confirmation of the results through more complex in vitro and in vivo experimental models.” Id. Ioghen, et al. further teaches that: “The induction of differentiation of the SH-SY5Y cell line into dopaminergic neurons is usually the first step for developing in vitro experimental designs to study PD. The morphological aspects of the neurons and the low proliferation rate makes the differentiated cells resemble the primary mesencephalic dopaminergic neurons, while the undifferentiated cells are much closer to a cancerous type of cell, related to their neuroblastoma origin.” Ioghen, et al. at section 3. Therefore, not only were SH-SY5Y cells disclosed in the specification closer to cancerous cells than dopaminergic cells, but Applicant also did not no follow through with a PD in vivo model that may provide some confidence that the claim-recited lectin may treat PD, let alone neurodegenerative diseases other than AZ / dementia.
It is unpredictable what neurodegenerative diseases are modeled by in vitro assays that have no in vivo corroboration.
The specification therefore only discloses in vivo effects of the claim-recited lectin using an AZ / dementia model; and in vitro effects using two in vitro models: a thorough disclosure of SCO and MPP+ effects in undifferentiated SH-S75Y cells with the claim-recited lectin; and a singular assessment of neurite outgrowth in PC12 cells with the lectin at Table 5. However, a “neurite outgrowth” assay in PC-12 cells is insufficient to cure the deficiencies laid out above because it is unpredictable how results obtained in vivo with one SCO AZ / dementia animal model will translate to the treatment of “neurodegenerative diseases” in general, let alone how a PC-12 cell “neurite outgrowth” assay using MPP+ cures this deficiency. To address this issue, a brief assessment of the state of the art of translating in vitro results to preventing or treating neurodegenerative diseases is presented herein, showing that in vitro results are just a starting point for demonstrating therapeutic effect, and that a majority of “promising” candidate drugs fail to actually treat the targeted neurodegenerative disease. Therefore, the MPP+ PC-12 “neurite outgrowth” results in view of the SCO AZ / dementia animal model results does not demonstrate the treatment or prevention of a PD, let alone “neurodegenerative disease” in general.
El Elhaj et al. ("Exploring Neurodegenerative Diseases: Bridging the Gap between in vitro and in vivo Models." Current Pharmaceutical Design (2025)) is a review discussing the strengths and weaknesses of in vitro vs in vivo models for neurodegenerative disease translational research. El Elhaj et al. at conclusion. El Elhaj et al. teaches: “In vitro models provide cost and complexity reduction, environment control, and high-throughput screening of potential therapeutic agents compared to in vivo models. Nevertheless, they possess constraints, including the absence of intricate interactions that transpire in the entire organism and the inability to reproduce the disease progression completely.” El Elhaj et al. at abstract. Therefore, in vitro models are a starting point that may suggest a therapeutic holds promise to prevent or treat a neurodegenerative disease, but still requiring corroboration from in vivo models.
Kim et al. ("Alzheimer’s disease: key insights from two decades of clinical trial failures." Journal of Alzheimer’s Disease 87.1 (2022): 83-100) is review of two decades of clinical trials results for AZ therapeutics. Kim et al. at title. Kim et al. teaches: “The two recent reported phase III successes of aducanumab and oligomannate are very encouraging; however, we are awaiting real-world validation of their effectiveness. These two successes against the 98 failures gives a 2.0% phase II and III success rate since 2003, when the previous novel compound was approved.” Kim et al. at abstract. Therefore, Kim et al. teaches it is very unpredictable which promising therapeutics actually prevent or treat a disease in vivo. In the instant case, disclosure of a single PC-12 “neurite outgrowth” assay and results obtained from undifferentiated SH-S75Y cells does not cure the deficiency that the specification only discloses in vivo results that read on AZ / dementia because it is highly unpredictable how the in vitro results will translate into treating or preventing all the “neurodegenerative diseases” encompassed by the claims.
It is unpredictable if a neurodegenerative disease can be “prevented” even if can be “treated.”
The claims recite a method of treatment or prevention of neurodegenerative disease. Although the examples may demonstrate some prophylactic effects of the claim-recited lectins for AZ / dementia (e.g., the in vivo model of Example 5 pre-treats the mice with the lectin for 14 days before administering the SCO AZ / dementia model), this does not rise to the level of showing “prevention” of neurodegenerative disease because the mice still ultimately developed the (SCO AZ / dementia model) neurodegenerative disease.
The Merriam-Webster dictionary defines the term “prevent” as: “to keep from happening or existing.” It gives the example of preventing a war, which means no war occurred. (www.merriam-webster.com/dictionary/prevent)
The Merriam-Webster dictionary defines the term “treat” as: “to care for or deal with medically or surgically.” It gives the example of treating a disease. (www.merriam-webster.com/dictionary/treat)
Example 5 shows e.g., that mice pre-treated with the claim-recited lectin had an intermediate Mean Transfer Latency Time (MTLT) in the Passive Avoidance Test compared to negative and positive SCO controls. See instant Table 10 (negative controls had a MTLT of 135.7 seconds; positive controls had a MTLT of 56.93 seconds; mice pre-treated with the claim-recited lectin had intermediate MTLTs of 75.81-85.26 seconds). The mice therefore still developed symptoms of the SCO AZ / dementia neurodegenerative disease, albeit to a lesser extent than the positive SCO control. Accordingly, “prevention” of neurodegenerative disease was not demonstrated in the instant specification; “treatment” was demonstrated because the SCO model was dealt with medically (i.e., by administering the claim-recited lectin), and a reduced form (i.e., not a prevention) of the SCO neurodegenerative disease resulted. It is therefore highly unpredictable if the claim-recited lectins can “prevent” the occurrence of any of the claim-recited neurodegenerative diseases since it did not prevent development of AZ / dementia symptoms in the in vivo SCO AZ / dementia model shown in Example 5.
The above therefore demonstrates that preventing AZ / dementia, let alone “neurodegenerative disease,” with the claim-recited lectins is highly unpredictable, if even possible. Therefore, without actually performing the required experiments, it is unpredictable which members of the instantly claimed genus “neurodegenerative disease” can be prevented with the claim-recited recombinant lectin proteins, and especially with recombinant lectin proteins having at least 75% homology to SEQ ID NO: 4 (i.e., claim 10).
It is unpredictable which fragments and/or variants of SEQ ID NO: 4 may prevent or treat neurodegenerative diseases.
Claim 10 recites that the recombinant lectin protein amino acid sequence may have “at least 75%, 80%, 90%, 95%, 96%, 97%, 98% or 99% homology to SEQ ID NO.4.” This claim therefore encompasses hundreds of fragments and variants of SEQ ID NO: 4 having at least 75% homology to SEQ ID NO: 4. The specification indicates SEQ ID NO: 4 is WT S. rolfsii lectin at page 16 line 18. The specification indicates the S. rolfsii lectin has affinity for TF and Tn antigen at page 4, line 11. The specification does not disclose which fragments / variants encompassed by “at least 75%” homology may retain these functional properties or still be considered a S. rolfsii lectin.
In contrast, the specification only discloses the use of SEQ ID NO: 1, which varies from 141 AA-long SEQ ID NO: 4 by substitutions: N14D, E113Q, and E123Q.
The claims recite functional language of the recombinant lectin, such as prevents or treats neurodegenerative disease, however a definition by function does not suffice to define the genus because it is only an indication of what the recombinant lectin does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. It is therefore highly unpredictable which of the 100s of recombinant lectin proteins encompassed by claim 10 have the required function. To address this issue, a brief assessment of the state of the art of the consequences of fragmenting proteins or peptides is provided below, which demonstrates the general principle that it is highly unpredictable what biological activity fragments of the recombinant lectin protein encompassed by claim 10 will have, let alone for treating or preventing the genus “neurodegenerative disease.”
Souza‐Silva et al. ("Peptide fragments of bradykinin show unexpected biological activity not mediated by B1 or B2 receptors." British Journal of Pharmacology 179.12 (2022): 3061-3077) teaches regarding fragments of the 9 amino acid Bradykinin sequence: “BK-(1–7) and BK-(1–5) are produced in vivo from BK-(1–9). Both peptides induced NO production in all cell types tested. However, unlike BK-(1–9), NO production elicited by BK-(1–7) or BK-(1–5) was not inhibited by B1 or B2 receptor antagonists.” Souza‐Silva et al. at abstract. Therefore, it was unpredictable that fragments of this 9 amino acid sequence would have substantially different biological activity compared to the full-length amino acid sequence.
In contrast, Zablocki et al. ("Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor." Journal of medicinal chemistry 36.13 (1993): 1811-1819) teaches regarding a fragment of the 4 amino acid RGDF sequence that surprisingly: “[p]reviously, we had shown that the inherent inhibitory potency of Arg-Gly-Asp-Phe [RGDF] for disrupting the fibrinogen-GP Ilb-IIIa interaction can be enhanced 15-fold by removing the Arg-NH2 and the Arg-Gly amide bond to obtain 8-guanidinooctanoyl-Asp-Phe[GOA-Asp Phe]” Zablocki et al. at introduction. In other words, the fragment of the 4 amino acid sequence showed a large increase in inhibitory activity compared to the full-length tetrapeptide.
The above juxtaposition of a fragmenting a short amino acid sequence resulting in substantially different biological activity as illustrated by Souza‐Silva et al. compared to fragmenting a different short amino acid sequence resulting in a large increase in (inhibitory) activity illustrated by Zablocki et al. shows it is very unpredictable what effects will be obtained with all the possible fragments and variants of SEQ ID NO: 4 encompassed by claim 10. Therefore, without performing the required experiments it is wholly unpredictable which fragments and variants having at least 75% homology to SEQ ID NO: 4 may retain biological activity, let alone biological activity that prevents or treats “neurodegenerative diseases” in general.
6) the amount of direction or guidance provided by the inventor:
The specification discloses: assessments undifferentiated SH-SY5Y cell viability when exposed to MPP+ with and without pretreatment with the recombinant lectin of SEQ ID NO: 1 (Examples 1-2); assessments differentiated PC-12 cell neurite outgrowth when exposed to MPP+ with and without treatment with the recombinant lectin (Example 3); measurements of biomarkers in undifferentiated SH-SY5Y cells when exposed to MPP+ or SCO with and without pretreatment with the recombinant lectin of SEQ ID NO: 1 (Examples 4); and in vivo behavioral tests and histopathology of mice exposed to SCO with and without pretreatment with the recombinant lectin of SEQ ID NO: 1 (Examples 5). The specification does not disclose the administration of any recombinant lectin other than the recombinant lectin of SEQ ID NO: 1.
The specification therefore only discloses in vitro models of neurite outgrowth with differentiated PC-12 cells, viability and biomarker assessments of undifferentiated SH-SY5y cells, and an in vivo AZ and dementia model using a recombinant lectin protein consisting of SEQ ID NO: 1. Given the evidence above, one of skill in the art could not reasonably extrapolate the instant findings regarding treating AZ and dementia with the recombinant lectin protein consisting of SEQ ID NO: 1 to preventing and/or treating the genus “neurodegenerative disease” with a recombinant lectin protein having at least 75% homology to SEQ ID NO: 4 (or any recombinant lectin proteins having homology less than 100% to SEQ ID NO: 1-4). It would also be undue experimentation to confirm which of the 100s of recombinant lectin proteins encompassed by claim 10 prevent and/or treat which “neurodegenerative diseases.”
8) the quantity of experimentation needed to make or use the invention:
It would be undue experimentation to make or use the invention encompassed by the breadth of the claims because 100s of recombinant lectin proteins would need to be made and evaluated for functionality with every known “neurodegenerative disease”; Applicant has only made and evaluated recombinant lectin protein consisting of SEQ ID NO: 1, and only tested it in the context of: AZ and dementia.
In conclusion, the claimed invention does not provide enablement for prevention and/or treatment of the genus “neurodegenerative disease” with the claim-recited lectins; the claimed invention provides enablement for treating AZ and dementia with a recombinant lectin protein consisting of SEQ ID NO: 1-4. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
9. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Presently amended claim 9—and claims 10-13, which depend therefrom—are rejected for reciting: “administering to the subject an effective amount of a recombinant lectin protein.” The specification provides a definition for a “therapeutically effective amount” of recombinant lectin protein at para. [0060], but the specification does not provide a definition for an “effective amount” of recombinant lectin protein. It is therefore unclear if the “effective amount” of lectin protein recited in the claim is the same as the “therapeutically effective amount” of recombinant lectin protein described in the speciation. Appropriate clarification and/or correction is required.
Pertinent Art
10. The prior art made of record and not relied upon is considered pertinent to Applicant’s disclosure:
Peppa et al. ("Molecular cloning, carbohydrate specificity and the crystal structure of two Sclerotium rolfsii lectin variants." Molecules 20.6 (2015): 10848-10865) (provided by Applicant); discloses that SSR1 (i.e., instant SEQ ID NO: 1) and SSR2 (i.e., instant SEQ ID NO: 2) are two different recombinant variants of SRL (i.e., instant SEQ ID NO: 4). All three recognize TF antigen, but only SSR1 (SEQ ID NO: 1) binds to Tn antigen (GalNAcα-Ser/Thr). The glycan array analysis of the variants shows that SSR1 (SEQ ID NO: 1) recognizes TF antigen with high affinity similar to SRL (SEQ ID NO: 4) but showed highest affinity towards the sialylated Tn antigen, unlike SRL (SEQ ID NO: 4). The carbohydrate binding property of SSR2 (SEQ ID NO: 2) was shown to be unaltered compared to SRL (SEQ ID NO: 4).
Lalezari et al. ("P2–006: Tn antigen in the brain: a newly recognized glycoprotein in Alzheimer's disease." Alzheimer's & Dementia 9 (2013): P347-P348); discloses that Tn antigen expression is elevated in the brains of AZ patients.
Swamy et al. (WO 2010/095143, published August 26, 2010); Swamy et al. is directed to uses of the recombinant lectins as cancer therapeutics (see e.g., Swamy et al. at field of invention). The instant specification at paragraphs [0082]-[0083] indicates SEQ ID NO: 1 corresponds to Rec-2 of Swamy et al., and SEQ ID NO: 2 corresponds to Rec-3 of Swamy et al. Swamy et al. shows that the two SEQ ID NOs had significantly different activity in cancer context, e.g.: binding to COLO-205 cells (Table 1 shows a significant 24% difference in binding between the two SEQ ID NOs).
Jacques et al. ("Lectin from Canavalia brasiliensis (ConBr) protects hippocampal slices against glutamate neurotoxicity in a manner dependent of PI3K/Akt pathway." Neurochemistry international 62.6 (2013): 836-842); discloses ConBr lectin as effective for treating a cause of some neurodegenerative diseases—glutamate neurotoxicity.
Conclusion
11. No claim is allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON R SCHWECHTER whose telephone number is (571)272-1270. The examiner can normally be reached M-Th 7-5 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford can be reached at 20857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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