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 .
DETAILED ACTION
The amendment to the claims filed after non-final office action on February 26, 2026 is acknowledged. Claims 1, 6, 8, 22, 27 were amended, claims 2, 9-21, 23, 29-47 were canceled and claim1, 3-8, 22, 24-28 are pending in the instant application. The restriction was deemed proper and made final previous office action.
Claims 5, 26 are withdrawn as being drawn to a non-elected species/invention. Claims 1, 3-4, 6-8, 22, 24-25, 27-28 are examined on the merits of this office action.
*After further review, a second Non-Final follows due to a new Double patenting rejection.
Withdrawn Rejections/Objections
The rejection of claims 6, 8 and 27 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in view of amendment of the claims filed 2/26/2026.
Claim Rejections - 35 USC § 112, first paragraph
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, 3-4, 6-8, 22, 24-25, 27-28 remain 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 promoting inducing new neural cells in patients that have had specific neurodegenerative events is not enabling the full scope of inducing generation of new neural cells in a patient suffering from a neurodegenerative event using the breadth of transferrin and lactoferrin species encompassed by the claim.. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
To comply with the enablement requirements of 35 U.S.C. §112, first paragraph, a specification must adequately teach how to make and how to use a claimed invention throughout its scope, without undue experimentation. Plant Genetic Systems N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003). There are a variety of factors which may be considered in determining whether a disclosure would require undue experimentation. These factors include: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The Nature of the Invention/ The breadth of the claims
The claims broadly encompass transferrin and lactoferrin proteins, mutants, fragments and derivatives (based on definition in specification, see paragraphs 0016, 0030) for inducing neurogenesis or neuronal differentiation. No sequence boundaries, motifs, or functional assays are defined that would allow a skill artisan to identify which among the vast number of possible variants would possess the desired property. The breadth of the genus far exceeds the embodiments actually demonstrated. Because the mechanism is uncertain, extrapolating the limited example to the entire claimed genus would require extensive screening/testing.
The State of the Prior Art
At the time of filing, transferrin and lactoferrin were well-known iron biding proteins, and their apo/holo forms, purification and recombinant production were established in the art. However, the art does not describe or predict neurogenic activity for either protein, nor did it disclose which mutants, fragments or structural variants would maintain or enhance such activity.
Yong teaches that “Recent advancements in lactoferrin research have uncovered that lactoferrin does function not only as an antimicrobial protein but also as an immunomodulatory, anticancer, and neuroprotective agent” (see abstract).
The specification does not identify any structural features responsible for neurogenesis, leaving a skilled artisan without guidance when attempting to determine which variants within the large transferrin/lactoferrin families would be operative. Thus, although the base proteins were known, the claimed breadth involving unspecified variants was not enabled by the prior art.
The Predictability or Unpredictability of the Art/ The Relative Skill of Those in the Art
The field of protein based neuro-differentiation is highly unpredictable. Small sequence changes or glycosylation differences can drastically alter receptor affinity, uptake or signaling activity. Without knowledge of the critical structural determinants, one skilled in the art could not predict which mutants, fragments or homologs would possess comparable neurogenic potential. As a result, substantial experimentation would be required to identify additional active species. While artisans skilled in protein biochemistry and neuronal cell culture could reproduce the specific SH-SY5Y experiments described, identifying and verifying all functional variants within the claimed genus would require inventive skill and extensive experimentation beyond routine capabilities.
Amount of Guidance/ The Presence or Absence of Working Examples
The specification provides limited guidance. It discloses only the use of the two wild type human apo-forms in a specific SH-SY5Y cell based assay. It does not define functional domains, critical residues, or parameters governing activity. The statement of “functional mutants or fragments thereof” may be used, without criteria for activity or examples, leaves the skilled artisan to determine efficacy solely through trial and error. Only two working examples-apo transferrin and apo-lactoferrin are provided. The claims, however, encompass multiple additional embodiments (mutants, fragments, derivatives an non-human homologs) for which no data or guidance are offered. The limited number of tested species cannot justify the breadth of the genus.
One of ordinary skill in the art would not consider the examples provided in the instant specification to be representative of the full scope of the claimed genus.
The Quantity of Experimentation Necessary
Considering the factors above, the skilled artisan would be burdened with undue experimentation in determining if one of the variants, mutants, fragments encompassed by the claims would be effective at promoting/inducing generation of new neural cells. The experimentation required represents years of inventive effort. 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.
Therefore, in view of the Wands factors, the claims appear to require undue experimentation to use the full scope of the claimed invention.
Response to Applicant’s Arguments
Applicants argue “According to the Examiner, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, for use the invention
commensurate in scope with these claims. Id. Applicant respectfully disagrees. Applicant respectfully submits that when the Wands factors are applied to the pending claims, the specification is fully enabling.
Firstly, Applicant would like to draw attention to the fact that the present invention is about
neurogenesis: the promotion and induction of forming new neural cells. No reference to Asthma
is made in the present invention. Secondly, under the sections "the nature of the invention" and "the breadth of the claims", the Examiner asserts that the claim broadly encompasses transferrin and lactoferrin proteins, mutants, fragments and derivatives for inducing neurogenesis or neuronal differentiation and no sequence boundaries, motifs or functional assays are defined that would allow a skill artisan to identify which among the vast number of possible variants would possess the desired property. See Office Action at page 4. The Examiner further asserts that breadth of the genus far exceeds the embodiments actually demonstrated and because the mechanism is uncertain, extrapolating the
limited example to the entire claimed genus would require extensive screening/testing. Id.
Applicant submits that these two Wands factors weigh in favor of enablement. The nature of the invention relates to methods of promoting and/or inducing generation of new neural cells in a patient that has suffered a neurodegenerative event. It would be well within the purview of one skilled in the art to recognize the iron saturation content is critical in getting the remarkable neurogenetic effect found by the present inventors when transferrins were used in the context of neurodegenerative diseases. Specification at [0101]-[0102]; see also Specification at Examples 6, Figure 6B and Table 1. Furthermore, the specification states specific mutant forms of transferrin that are inducing neurogenesis such as i) Y188F mutant N lobe (SEQ ID NO: 3); ii) Y95F/Y188F mutant N lobe (SEQ ID NO: 4); and iii) Y426F/Y517F mutant C lobe (SEQ ID NO: 5). The present specification shows that both transferrin and lactoferrin include two lobes (N- and C-lobes) with each lobe binding a single iron atom and as such, they can bind up to two iron atoms or ions per molecule. Specification at1 [0041]. For example, a review by Baker3 concerning the structural and functional similarities between transferrin and lactoferrin:
The ligands for the bound Fe3+ ion are the same in both lobes and in all higher transferrins (Lf, sTf, and oTf). These ligands comprise two tyrosine residues, one aspartic acid and one histidine (Tyr92, Tyrl92, Asp60, and His253 in the N-lobe of Lf), together with two oxygen atoms from the synergistically bound CO32- ion (Fig. 2)." This set of ligands is responsible for the binding to iron with high affinity but reversibly. Moreover, the synergistic relationship between metal binding and anion binding is referred as one of the unique features not seen in other metal-binding proteins. Thus, the information provided in the review relating to the common structural features shared only by transferrin and lactoferrin provides strong evidence of the enablement of the presently claimed invention. Under the section, "the state of the prior art", the Examiner asserts that at the time of filing, transferrin and lactoferrin, purification and recombinant production were well known iron binding proteins but their apo/holo forms, purification and recombinant production were established in the art but does not describe or predict the neurogenic activity for either protein or disclose with mutant, fragment or structural variant would maintain such activity. However, the Examiner does not take into account that the neurogenic effect provided by
transferrin and lactoferrin is reported for the first time by the present inventors in the current patent application. This neurogenic effect, reported for the first time here, is well-based on the ability of transferrin to induce differentiation of the SH-SY5Y cells when a therapeutically effective amount of transferrin or lactoferrin was administered to the patient who underwent a neurodegenerative condition and has an iron saturation of less than about 20% as currently claimed in the current
application. The Examiner also asserts that "predictability or unpredictability of the art" and "the
relative skill of those in the art" rises due to the lack of knowledge of the critical structural determinants, one skilled in the art could not predict the which mutant, fragment or homologs possess comparable neurogenic potential. See Office Action at page 4. Applicant respectfully disagrees. Applicant submits that the specification of the present invention shows successful neurogenesis of SH-SY5Y cells when effective amount of transferrin or lactoferrin was administered to the patient who underwent a neurodegenerative condition and provided that apotransferrin or apolactoferrin has an iron saturation of less than about 20%. The specification showed that although, Holo-transferrin (HoloTf), the highly iron-saturated form of transferrin, was also unable to induce differentiation of the SH-SYSY cells, Apo-Transferrin and Apo-Lactoferrin with a content below 20%, provided a remarkable neurogenic effect on SH-SYSY cells. Specification at Examples 4 and Figure 4. The Examiner also asserts that "amount of guidance", "the presence or absence of working examples" and "quantity of experimentation necessary" rises due to limited guidance, one skilled in the art would not consider the examples provided in the instant specification to be representative of the full scope of the claimed genus and the skilled artisan would be burdened with undue experimentation. See Office Action at page 5. Applicant respectfully disagrees. Applicant submits that the specification provides example that shows that the iron
saturation content is critical in getting the remarkable neurogenetic effect in the claimed method for promoting generation of new neural cells. The specification further provides sufficient experimentation necessary to enable the methods, sufficient direction or guidance to enable the methods, and several example protocols for promoting and/or inducing generation of new neural cells in a patient that has suffered a neurodegenerative event by administering a therapeutically effective amount of transferrin or lactoferrin when the patient has an iron saturation of less than about 20% such that one skilled in the art would not be required to perform any additional experiments to practice the claimed invention. See Specification at Example 6 and Figure 6B. Therefore, because the specification discloses the claimed invention that bears a reasonable correlation to the entire scope of the claims, the enablement requirement of 35 U.S.C. § 112 is satisfied. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Applicant respectfully requests withdrawal of the rejection.
Applicant’s arguments have been fully considered but not found persuasive. At the outset, the Examiner acknowledges Applicant’s statement regarding the reference to “asthma” in the prior Office Action. This reference was included in error from a template and is not relied upon in the present rejection. The rejection is based solely on whether the specification enables the full scope of the claimed invention. Applicant argues that the specification is enabling because it demonstrates neurogenesis through differentiation of SH-SY5Y cells and neural progenitor cells and provides guidance regarding iron saturation (less than 20%). While these data are acknowledged, they do not establish enablement commensurate in scope with the claims. The claims require promoting and/or inducing generation of new neural cells in a patient that has suffered a neurodegenerative event. The specification primarily demonstrates in vitro differentiation in cell based models (e.g. SH-SY5Y cells and cultured neural progenitor cells). Such in vitro results do not reasonably establish that the claimed proteins will induce generation of new neural cells in vivo in a patient, particularly within the complex biological environment associated with different neurodegenerative conditions. The limited in vivo data cited by Applicant relates to functional improvement in an animal model and does not demonstrate the claimed generation of new neural cells in any patient with any neurodegenerative event.
Applicant further argues that the identification of iron saturation levels (less than about 20%) provides sufficient guidance to practice the invention without undue experimentation. However, while iron saturation may be a relevant parameter, it does not adequately define which among the broad scope of transferrin and lactoferrin species encompassed by the claims, including mutants, fragments, derivatives and homologs, will exhibit the claimed neurogenic activity. The specification does not identify structural features, sequence requirements, or other criteria that would allow a person of ordinary skill in the art to predict which variants would be functional. Accordingly, substantial experimentation would still be required to identify functional embodiments across the full scope of the claims.
Applicant also contends that the disclosure of transferrin, lactoferrin and certain mutants provides sufficient representative support for the claimed genus. This argument is not persuasive. The specification provides a limited number of working examples, primarily involving apo transferrin and apo lactoferrin in specific in vitro assays, with limited additional examples of mutants. The claims, however, encompass a much broader genus, including unspecified fragments, derivatives and homologs. The limited number of tested species is not representative of the full scope of the claimed genus, and the specification does not provide sufficient guidance to extrapolate which additional variants would possess the claimed activity without undue experimentation.
Applicant further argues that the structural and functional similarities between transferrin and lactoferrin, as described in the prior art support enablement. However, while structural features of these proteins were known, the specification itself indicates that the neurogenic activity was not previously recognized. The specification does not identify the structural determinants responsible of the claimed activity. Therefore, a person of ordinary skill in the art would not be able to reasonably predict which variants, fragments, or homologs would retain the claimed function, particularly in view of the unpredictability of protein function in biological systems.
Finally, Applicant asserts that one skilled in the art would not be required to perform additional experimentation to practice the claimed invention. The Examiner disagrees. Given the breadth of the claims and the limited guidance provided in the specification, a skilled artisan would be required to engage in substantial testing to identify which protein variants within the claimed genus exhibit the claimed activity and determine conditions under which generation of new neural cells can be achieved in vivo in a patient suffering from a neurodegenerative condition (which vary in their pathogensis and etiology). This is considered undue experimentation. In view of the foregoing, and considering the wands factors, the specification does not enable the full scope of the claimed invention without undue experimentation.
Claim Rejections - 35 USC § 112, first paragraph
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, 3-4, 6-8, 22, 24-25, 27-28 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Scope of the claims
The claims encompass compositions and methods employing transferrin and or lactoferrin, including wild type, recombinant functional mutants, fragments (see paragraphs 0016, definition of lactoferrin, paragraph 0030, definition of lactoferrin), for inducing neurogenesis or neuronal differentiation. The claimed genus therefore spans multiple structurally distinct proteins and potential derivatives across species. This broad scope requires the specification to reasonably convey possession of the full range of transferrin and lactoferrin related embodiments having the claimed activity.
Therefore, to meet the written description requirement of 35 U.S.C. § 112, first paragraph, the specification must disclose a representative number of species that meet both the structural and functional limitations of the genus or the specification and/or the prior art must identify the structural elements that correlate to the claimed function in a manner that demonstrates to one of ordinary skill in the art that Applicant was in possession of the claimed genus at the time the application was filed. In the instant case, the specification must establish which of peptides encompassed by the claims (with the definition of lactoferrin and transferrin) that satisfy the structural limitations of the claim are also capable of promoting or inducing neural cells.
Actual Reduction to Practice
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Applicant’s reduce to practice the following: Examples 1-9 evaluate apo-transferrin and apo-lactoferrin in SH-SY5Y neuronal cell assays. Example 9 also looks at use of ApoTF in a mouse model of Parkinsons disease. However, the data are limited to the wild type human apo forms and do not extend to other embodiments encompassed by the claim due to the definition of lactoferrin and transferrin in the specification (i.e. functional mutants, fragments or non-human homologs). No sequence variants or structure-activity correlations are provided that would reasonably convey possession of the entire claimed genus.
One of ordinary skill in the art would not consider the examples provided in the instant specification to be representative of the full scope of the claimed genus.
Therefore, the instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
Sufficient relevant identifying characteristic
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination thereof.
The specification defines Transferrin as a mammalian iron binding glycoprotein comprising two homologous lobes, each binding iron with apo and holo forms distinguished by iron levels (paragraphs 0014-0022). Additionally, the specification states “By “transferrin” the current specification is to be construed as meaning a therapeutically effective amount of: a wild type (mammalian, preferably human) transferrin protein, a functional mutant thereof, a functional fragment thereof, or combinations thereof (see paragraph 0016).
Lactoferrin is defined as a mammalian milk glycoprotein of analogous bilobal structure capable of binding iron with apo/holo states. Additionally, the specification states “By “lactoferrin” the current specification is to be construed as meaning a therapeutically effective amount of: a wild type (mammalian, preferably human) lactoferrin protein, a functional mutant thereof, a functional fragment thereof, or combinations thereof” (see paragraph 0030).
The specification lacks sufficient structural identifying characteristics of the variants, mutants or functional fragments of lactoferrin or transferrin that would retain the desired functional activity of inducing new neural cells or stimulating neural cell development.
Physical and/or chemical properties:
The specification discloses that both proteins (wild type) bind through homologous lobes and that their iron saturation state can be measured. While the examples confirm that each protein is biologically active in SH-SY5y cells (full length proteins), they do no establish a unifying structural basis that would demonstrate possession of all transferrin/lactoferrin variants/fragments etc..that are encompassed by the claims.
Functional characteristics when coupled with a known or disclosed correlation between function and structure:
The examples indicate that apo-transferrin and apo-lactoferrin can both induce neuronal differentiation, but the specification lacks how these proteins achieve this effect. There is nothing that describes what amino acids/structure of the proteins are required for the desired functional properties.
Without the structure/function correlation, the artisan cannot discern whether the observed activity is due to a common feature (iron free state, glycosylation patter, amino acid sequence) or due to unrelated mechanisms specific to each protein. Consequently, while both proteins are shown to be active, the disclosure does not support possession of a functional genus encompassing all related transferrin based or lactoferrin based molecules encompassed by the claims with the same functional effects.
Method of Making
The specification states that transferrin and lactoferrin may be obtained from human plasma and milk, respectively, or produced recombinantly (see paragraph 0015, 0030). These teachings establish that the wild type proteins can be prepared using routine methods but not describe production or identification of functional mutants, fragments or derivatives encompassed by the claims. The absence of such detail further limits the scope of described embodiments to the specific apo-forms tested.
Conclusion
In conclusion, the specification fails to provide adequate written description support for the broad genus encompassing lactoferrin and transferrin as defined in the specification. The disclosure lacks sufficient structure function correlation, physical/chemical data and examples that demonstrate possession of the full scope of the claimed genus. Accordingly, only specific peptides reduced to practice, satisfies the written description requirements of 35 U.S.C. 112, first paragraph.
Response to Applicant’s Arguments
Applicants argue “Without acquiescence and solely in the interest of advancing prosecution of the present application, claim 1 is amended and recites a method of promoting and/or inducing generation of new neural cells in a patient that has suffered a neurodegenerative event.......wherein the therapeutically effective amount of transferrin or lactoferrin administered to the patient has an iron saturation of less than about 20%." Thus, amended claim 1 recites a method of promoting and/or inducing generation of new neural cells where the patient specifically has an iron saturation of less than about 20%. Example 6 of the Specification as filed provides express disclosure of methods for "Role of Iron Saturation in Transferrin Efficacy." See Specification at Examples 6, Figure 6B and Table 1. Applicant respectfully submits that [0185] and [0187]-[0188] (reproduced below) of Example 6, for example, provides adequate written description such that one skilled in the art would conclude Applicant possessed a method of promoting and/or inducing generation of new neural cells as recited in the claims. Example 6 and Figure 6B provides a description for the feature that the iron saturation to be administered with the transferrin or lactoferrin needs to be below 20%. The iron saturation is the most essential feature to get the neurogenetic effect from transferrin or lactoferrin. Undifferentiated SH-SY5Y cells were treated as described in Example 1.
Neurite growth was assessed by imaging and image analysis. At the time of analysis, a lOx solution of Tubulin Tracker (Molecular Probes, T34075) and Hoechst 33342 (Molecular Probes #H3570) nuclear stain was prepared. Briefly, Tubulin Tracker dissolved in DMSO was diluted 1:1 with Pluronic F-127 and further diluted into HBSS to generate a lOx solution. Hoechst 33342 was added to the HBSS-Tubulin Tracker solution at 10 pg/mL to generate at lOx nuclear stain. The lOx staining solution (10 pL) was added directly to treated assay wells and incubated at 370 C. for 30 minutes. Following incubation, 110 pL of 0.4% Trypan Blue was added directly to assay wells and imaged on a Molecular Devices Nano imaging instrument. Nine images/well were acquired in the blue (Nuclei) and green (Tubulin) fluorescent channels for each image. After obtaining images, the MetaExpress Neurite Outgrowth analysis module (Molecular Devices) was used to identify cell bodies and quantify neurites. The total number of neurite branches were divided by the total number of cells imaged to account for different numbers of cells. The Outgrowth Fold Change was determined by setting the untreated control to a value of 1 with all other treatments shown relative to untreated control. [0187] ApoTf (<0.3% Saturation) and, HoloTf (100% Saturation) were prepared after purification of transferrin from pooled human plasma as outlined in von Bonsdorff, vide supra. The various iron saturation contents were generated by mixing ApoTf and HoloTf to generate the indicated percent saturations plotted in FIG. 6B. [0188] From FIG. 6A we see that all ApoTf preparations (ApoTf A-D), even the sample with a protein purity of only 94%, were able to induce neurogenic differentiation of SH-SY5Y. FIG. 6B illustrates effect the degree of iron saturation had on the ability of transferrin to induce differentiation of the SH-SY5Y cells. In this example, ApoTf or HoloTf with protein purities of at least 99% were mixed in various ratios to determine the effect of iron saturation/content. Transferrin with an iron saturation content less than 30% showed neurogenic potential. Furthermore, Applicant also submits that f [0169]-[0173] Example 3 provides adequate
written description exhibiting that all the different forms of apoTfs (wild type, recombinant and mutant) when tested, with the iron saturation below 20%, were effective in providing the neurogenetic effect as shown in Figure 3B. See Specification at Examples 3 and Figure 3B. [0169] The present inventors further sought to determine whether a reduction of transferrin's iron-binding activity by mutation of the N-terminal iron-binding site was sufficient to mediate neurogenesis. [0170] Undifferentiated SH-SYSY cells were treated as described in Example 1. Neurite growth was assessed by imaging and image analysis. At the time of analysis, a lOx solution of Tubulin Tracker (Molecular Probes, T34075) and Hoechst 33342 (Molecular Probes #H3570) nuclear stain was prepared. Briefly, Tubulin Tracker dissolved in DMSO was diluted 1:1 with Pluronic F-127 and further diluted into HBSS to generate a lOx solution. Hoechst 33342 was added to the HBSS-Tubulin Tracker solution at 10 pg/mL to generate at lOx nuclear stain. The lOx staining solution (10 pL) was added directly to treated assay wells and incubated at 370 C. for 30 minutes. Following incubation, 110 pL of 0.4% Trypan Blue was added directly to assay wells and imaged on a Molecular Devices Nano imaging instrument. Nine images/well were acquired in the blue (Nuclei) and green (Tubulin) fluorescent channels for each image. After obtaining images, the MetaExpress Neurite Outgrowth analysis module (Molecular Devices) was used to identify cell bodies and quantify neurites. The total number of neurite branches were divided by the total number of cells imaged to account for different numbers of cells. The Outgrowth Fold Change was determined by setting the untreated control to a value of 1 with all other treatments shown relative to untreated control. All proteins were dosed at a final concentration of 0.2 mg/mL.
[0171] Plasma-derived human serum albumin (pdHSA) and ApoTf were obtained and purified from pooled human plasma; recombinant ApoTf (rec ApoTf; SEQ ID NO: 1), and the N-lobe mutant Tf (N-mut rec ApoTf; SEQ ID NO: 4) were obtained by cell culture expression from 293-6E cells. [0172] Briefly, wild-type human transferrin (SEQ ID NO:1) and N-lobe mutant human transferrin (SEQ ID 4) sequences were cloned into mammalian expression plasmids containing N-terminal 6xHIS tag and TEV cleavage sites. The expression plasmids were transfected into the 293-6E cell line, with subsequent harvest of proteins from the cell culture supernatant. Proteins were purified on NI-NTA columns and eluted after washing.
TurboTEV protease was used to cleave the N-terminal 6xHIS tag and additional amino acids from the transferrin proteins. Following TEV cleavage, the transferrin proteins were separated from cleaved 6xHIS tag and uncleaved protein by a second Ni-NTA capture column. The flow-through fraction of Ni-NTA capture column was then subject to low pH treatment to remove any potential residual iron bound to these proteins, buffer exchanged to PBS pH 7.4, concentrated, and sterile filtered for final use.
[0173] From FIG. 3B we see that plasma-derived human serum albumin (pdHSA) did not affect neurogenesis. However, both ApoTf and recombinant ApoTf did induce neurogenesis of SH-SYSY. The ApoTf mutant (N-mut rec ApoTf) with reduced iron- binding capacity was almost equal to that of ApoTf and rec ApoTf at inducing differentiation of the SH-SYSY cells. Iron-binding does not appear to be the sole mechanism of action for the neurogenic potential of ApoTf.
Applicant argues that amended claim 1 is adequately supported because the specification discloses that transferrin or lactoferrin having an iron saturation below about 20% promotes and or induces generation of new neural cells, citing Example 6, Figure 6B, Table 1 and Examples 1 and 3. Applicant further argues that apo transferrin preparations and certain recombinant or mutant apo transferrin proteins demonstrated neurogenic activity and therefore provide adequate written description support for the claimed invention. Applicant additionally contends that iron saturation is the essential feature responsible for the observed neurogenic effect. Applicants arguments have been fully considered but are not found persuasive. The written description rejection is not based solely on whether the specification demonstrates that certain apo transferrin or apo lactoferrin preparations can induce neuronal differentiation in SH-Sy5Y cells. Rather, the rejection is directed to whether the specifically reaonsbaly coveys possession of the full claimed genus at the time of filing. As presently claimed and defined in the specification, “Transferrin” and “lactoferrin” encompass broad functional genera including wild type proteins, recombinant proteins, functional mutants, functional fragments, derivatives, combinations thereof, and non human homologs. The claims therefore encompass numerous structurally distinct species beyond the limited proteins actually tested in the specification.
Applicant’s reliance on iron saturation levels does not overcome the rejection because the specification does not establish that iron saturation alone is sufficient to identify which members of the broad claimed genera possess the claimed neurogenic activity. While the cited examples demonstrate activity for certain apo transferrin and apo lactoferrin preparations under specific assay conditions, the disclosure does not provide a structure function correlation that would allow one skilled in the art to recognize which mutants, fragments, derivates, or homologs across the full scope of the claims would retain the claimed activity.
For example, Applicant cites Example 3 as demonstrating that wild type, recombinant ,and mutant apo transferrin were effective when iron saturation was below about 20%. However, the disclosure evaluates only a very limited subset of transferrin species, namely specific full length human apo transferrin proteins and a specific N lobe mutant. The specification does not disclose representative species spanning that breadth of the claimed genus, nor does it identify common structural features that correlation with the claimed neurogenic function across the full scope of transferrin and lactoferrin based embodiments.
Moreover, the specification itself indicates the reduced iron binding is not the sole mechanism responsible for neurogenic activity. Example 3 states that the “N mut rec ApoTF with reduced iron binding capacity was almost equal to that of ApoTF and rec ApoTF” and concludes that iron binding does not appear to be the sole mechanism of action for the neurogenic potential of ApoTF. Thus, Applicants own disclosure does not establish that iron saturation below 20% alone defines or predicts the full scope of operative species encompassed by the claims.
Additionally, the cited examples are limited primary to SH-SY5Y neuronal differentiation assays using specific human apo-proteins. The specification does not provide sufficient representative species or identifying structural characteristics demonstrating possession of the broader claimed functional genus encompassing fragments, derivatives, mutants and homologs of transferrin and lactoferrin generally.
Accordingly, while the specification may demonstrate possession of certain specific apo transferrin and apo lactoferrin embodiments, it does not reasonably convey possession of the full scope of the claimed genus as required under 35 U.S.C. 112(a). Therefore, the written description rejection is maintained.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3-4, 22, 24-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dalmau (US20140323409 A1, cited previously).
Claim interpretation: regarding the limitation of a “neurodegenerative event”, Applicant’s specification defines “neurodegenerative event” as follows, as used herein, the term “neurodegenerative event” refers to an event that causes the loss of structure and/or function of neural cells and includes the death of neural cells. The event may be an isolated one-off event/occurrence causing immediate neural cell damage or death (see paragraph 0060).
Dalmau teaches a method of treating brain ischemic stroke in patient comprising administering apo-transferrin to the patient (see claim 1). A patient that had an ischemic brain stroke meets the limitation of a patient that suffered a “neurodegenerative event”. Dalmau additionally teaches use of a therapeutically effective amount of the transferrin (see paragraphs 0037, 0040). Regarding the limitation of “promoting generation of new neural cells” (claim 1) and stimulating neural cell development (claim 22), Dalmau teaches the same method of the instant claims including the same patient population, a patient that suffered a neurodegenerative event, and administering the same drug and thus, the result oriented effect of promoting generation of neural cells (claim 1) or stimulating neural cell development (claim 22) would necessarily and inherently occur as a result of practicing the method of Dalmau. Regarding claims 1 and 22, Apo transferrin is considered iron free and thus would meet the limitations of less than about 20% iron saturation (see paragraph 0017). Regarding claims 3 and 24, Dalmau teaches use of human apo transferrin (see bottom of paragraph 0017). Regarding claims 4 and 25, Dalmau teaches use of recombinant human apo transferrin or derived from human (see paragraph 0041).
Response to Applicant’s Arguments
Dalmau discloses use of neuroprotection, but not of neurogenesis, and is silent
about the generation of new neuronal cells. The scientific distinction between "neuroprotection" (prior art) and "neurogenesis" (i.e., the formation of new neuronal cells, the invention) is highlighted in a review by Zhu et al.4. In the review, there is the neuroprotective therapy referring to pre-brain ischemia and a short period of time after ischemia to target the ultra-early and acute stages. On the other hand, there is the neurorestorative therapy referring to the intervention of the brain ischemia delay effect, including
angiogenesis, neurogenesis, and synaptic regeneration. This distinction is also evident from a review by Thomas Carmichael,5 which illustrates the progress of stroke in time (see figure). Ischemic stroke starts as an acute loss of blood flow to a region of the brain. This precipitates a cascade of direct damage in neurons, astrocytes, blood vessels (endothelial cells and pericytes), oligodendrocytes, microglia, and oligodendrocyte precursor cells. (...) Calcium- mediated proteolysis, lipolysis, and DNA degradation lead to necrotic cell death. There are other molecular actors in this initial neuronal cell death, including free radical formation in the disordered mitochondria. In total, this is the process of neuronal excitotoxicity, first prominently described in stroke in the late 1980s and the motive force behind many of the stroke clinical trials of the 1990s. The initial excitotoxic death of neurons is quickly irreversible and a re-analysis of preclinical animal modeling data and the experience of the failed stroke trials indicate that the initial phase of neuronal cell death is quite likely beyond the reach of clinical medicine as a therapeutic target. (...) Human imaging and rodent preclinical stroke models indicate that the ischemic penumbra will die and become part of the stroke core in roughly 2 days. In other words, in the acute period after stroke the core dies and the penumbra has 2 fates: it will either die and become part of the stroke core, or be salvaged by therapy and survive. It has been demonstrated that cell death occurs within minutes and hours after the ischemic event and, thus, any therapy dedicated to neuroprotection must be performed in the same time window. Otherwise, the neural cell will be dead and cannot be protected any more. Dalmau refers to the use of apo-transferrin for the treatment of brain stroke in order to reduce the damage caused after a brain stroke, i.e. to protect the still living neural cells and limit the consequences of the brain stroke. In Example 2.1 of Dalmau, apo-transferrin was administered directly after provoking ischemia, whereas in Example 2.2, apo-transferrin administration took place 50 minutes after provoking ischemia, and Example 2.3, apo-transferrin was administered about 100 minutes after ischemia was provoked. Hence, Dalmau discloses use of apo-transferrin for the treatment of brain stroke for neuroprotection, but not of neurogenesis, and is silent about "the generation of new neuronal cells" as recited in amended Claim 1. As discussed in the specification, while neuroprotection is beneficial prior to death of a neuron, neuroprotection does not benefit the patient once a neuronal cell is dead. Neurogenesis, on the other hand, benefits the patient after the insult because it can regenerate new neuronal cells. Hence, the use of transferrin in the present invention stimulates the neurogenesis or development of neural cells. Thus, the new technical effect enables to treat a new subgroup of patients, namely those where neural cell death has already occurred, thus leading to a true a new clinical situation. For at least the foregoing reasons, Applicant respectfully submits that Claim 1 is novel over Dalmau. For at least similar reasons mentioned above, amended independent Claim 22, which recites a method of stimulating neural cell development in a patient that has suffered a neurodegenerative event, is also novel over Dalmau.
Applicant argues that Dalmau discloses only neuroprotection following ischemic stroke and is silent regarding neurogenesis or generation of new neuronal cells. Applicant further argues that neuroprotection and neurogenesis are scientifically distinct processes, asserting that Dalmau merely protects surviving neurons during the acute post stroke window whereas the instant claims are directed to regeneration or development of new neural cells after neuronal death has occurred. Applicants arguments have been fully considered but not found persuasive. The claims are not limited to any particular mechanism, timing window, biomarker, histological endpoint, or quantitative assay demonstrating formation of newly generated neurons. Rather, the claims broadly recite “promoting and or inducing generation of new neural cells” or “stimulating neural cell development” in a patient having suffered a neurodegenerative event.
Dalmau teaches administration of apo transferrin to patients suffering ischemic stroke, which falls within Applicants own definition of a “neurodegenerative event” because stroke results in loss of neural cell structure and or function neuronal death. Dalmau further teaches therapeutic administration of apo transferrin to neural tissue following ischemic injury in order to promote recovery and reduce neurological damage. Applicant attempts to distinguish “neuroprotection” from “neurogenesis”. However, the instant claims do not recite a specific temporal distinction requiring treatment only after neuronal death has completed, nor do the claims exclude treatment during acute ischemic injury. The claims likewise do not require direct demonstration that newly generated neurons arise from stem or progenitor cells. As such, the broad functional language reasonably encompasses therapeutic processes involving neural repair, neural recovery, neural development, or preservation of neural cell populations following injury.
Moreover, Applicant’s arguments improperly import limitations from the specification into the claims. While Applicant cites scientific literature discussing differences between neuroprotection and neurorestoration, the claims themselves do not recite the narrower distinctions advanced in argument.
Additionally, Applicant’s own specification indicates that apo-transferrin administration produces the claimed neural effects. Dalmau teaches administration of the same therapeutic agent, apo transferrin, the same injured neural environment following ischemic stroke. Therefore, the functional effects recited in the claims would inherently result from practicing the prior method, even if Dalmau did not expressly recognize or label the effect as “neurogenesis”. Inherency does not require recognition in the prior art of the inherent property or result (see MPEP2112).
Further, Dalmau teaches administration of apo transferrin at time points following ischemic insult, including delayed administration after ischemia induction. Thus, Applicant’s argument that Dalmau is limited solely to immediate acute neuroprotection is not persuasive.
Claim(s) 1, 3-4, 6-8, 22, 24-25, 27-28 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ross (EP2977056, cited previously).
Claim interpretation: regarding the limitation of a “neurodegenerative event”, Applicant’s specification defines “neurodegenerative event” as follows, as used herein, the term “neurodegenerative event” refers to an event that causes the loss of structure and/or function of neural cells and includes the death of neural cells. The event may be an isolated one-off event/occurrence causing immediate neural cell damage or death (see paragraph 0060). Applicants further define “neurodegenerative event” to include neurodegenerative diseases (see claim 8 for example).
Ross teaches a composition for treating Alzheimer’s and Parkinson’s disease comprising administering apo-transferrin to the patient (see claim 1 and paragraph 0005 ). A patient that has Parkinson’s disease meets the limitation of a patient that suffered a “neurodegenerative event” given Applicants define to include neurodegenerative diseases (see claim 8 for example). Ross additionally teaches use of a therapeutically effective amount apo transferrin in a mammal model of cerebral artery occlusion (MCAo, which is also considered a neurodegenerative event) (see Example 6). Regarding the limitation of “promoting generation of new neural cells” (claim 1) and stimulating neural cell development (claim 22), Ross teaches the same method of the instant claims including the same patient population, a patient that suffered a neurodegenerative event (i.e. Parkinson’s disease or MCAo), and administering the same drug and thus, the result oriented effect of promoting generation of neural cells (claim 1) or stimulating neural cell development (claim 22) would necessarily and inherently occur as a result of practicing the method of Ross. Regarding claim 1, Apo transferrin is considered iron free and thus would meet the limitations of less than about 20% iron saturation (see paragraph 0004). Regarding claims 3 and 24, Ross teaches use of human apo transferrin (see paragraphs 0009, 0046). Regarding claims 4 and 25, Ross teaches use of recombinant human apo transferrin or derived from human (see paragraph 0009).
Regarding claims 6 and 27,Ross teaches wherein the transferrin is used in a conjugate or fusion with Fc domain (see paragraph 0017 and claim 4) to extend the half-life of the protein.
Regarding claims 7-8 and 28, Ross teaches treatment of Alzheimer’s, Parkinson’s and Huntington’s disease (see claim 1 and paragraph 0001) which are neurodegenerative diseases.
Response to Applicant’s Arguments
Applicant argues that “The Examiner alleged that paragraph [0005] of Ross teaches a composition for treating Alzheimer's and Parkinson's disease comprising administrating apo-transferrin to the patient. The applicant respectfully submits that this interpretation is incorrect. Ross refers to neurodegenerative diseases only as underlying conditions potentially associated with HIF dysregulation, not as therapeutic targets. No therapeutic treatment of neurodegeneration is disclosed or suggested. The Examiner further alleged that paragraph [0004] of Ross teaches the use of therapeutically effective amount of apo-transferrin in a mammal model of cerebral artery occlusion and paragraphs [0009] and [0046] of Ross teaches use of recombinant human apo-transferrin or derived from human. Ross teaches transferrin, possibly in combination with an iron-chelator (e.g., deferoxamine) or a PHD2 enzyme inhibitor, for use in the treatment of Hypoxia Inducible Factor (HIF)-related conditions, in particular associated with organ transplantation, ischemia, oxygen deprivation, interruption of blood during surgical intervention, or neurodegenerative disorders. The therapeutic strategy provided by Ross is based on modulating the HIF pathway, which plays a central role in cellular response to hypoxia and ischemia. Applicant respectfully submits that Ross does not define the therapeutic target of the invention but rather provides contextual background on one possible origin of HIF-related dysfunction. The main invention of Ross is the treatment of HIF-related pathological conditions via transferrin administration. Hence, Ross' invention is not directed to the treatment of neurodegenerative diseases by inducing or promoting growth of new neuronal cells, but to the modulation of HIF signaling in conditions where this pathway is impaired or dysregulated. Ross demonstrate the upregulation of HIF1-alpha and its downstream targets (e.g., Glut1,
VEGF) in neuronal and kidney cells following transferrin treatment, the protective effects in models of ischemia and hypoxia, including organ transplantation and stroke and that the lack of toxicity and synergistic effects with known HIF activators (e.g., DFO, IOX2), reinforcing the role of transferrin as a modulator of HIF signaling. Thus, Ross targets the underlying HIF-related mechanisms, which may be present in a variety of pathological contexts, including but not limited to ischemia, organ transplantation, and oxygen deprivation. In addition, Example 7 of Ross reports the protective effect of apotransferrin against Abeta 1-42 Toxicity, "[U]pregulation of the HIF pathway is known to play a protective role in a number of neurodegenerative diseases, including pathologies that result in destruction of nerve cells and neurons. Since treatment of SH-SY5Y upregulates HIF, treatment of cells with Apo- or Holo- transferrin should provide a protective effect on cells subjected to substances known to induce neurodegeneration. FIG. 7 highlights data assessing whether majorities of Apo- and Holo- transferrin could protect SH-SY5Y cells from the toxic effects of the known neurodegenerative toxin oligomerized Abeta 1-42 peptide (FIG. 7). SH-SY5Y neuronal cells cultured in growth media were treated with 4 mg/mL Apo-transferrin or Holo-transferrin for 24 hrs under normal oxygen levels. After 24 hrs, cells were treated with oligomerized Abeta1-42 peptide for an additional 72 hours. Following treatment with oligomerized Abeta1-42, cells were subjected to a ApoGlo caspase 3/7 activation assay. Control cells, untreated cells, were set to a normalized value of 1. The average caspase induction, relative to control cells, and standard deviations are shown for each treatment condition. Interestingly, these data show that both majority ApoTf and HoloTf protect SH-SY5Y cells from Abeta induced toxicity. These data also further confirm lack of inherent toxicity with either ApoTf or HoloTf". Ross at [0076] Example 7 discloses the administration of apotransferrin prior to the addition of the toxic substance (i.e., ß-amyloid protein), i.e. before the onset of any neurodegenerative condition. This means that any beneficial effect reported in Ross as a result of apoTf administration occurs in the absence of an established neurodegenerative disease. Therefore, Example 7 of Ross does not disclose the treatment of a neurodegenerative condition. Rather, it demonstrates a protective effect, whereby apotransferrin neutralizes the toxic effects of ß-amyloid protein by increasing HIF levels. The data in Example 7 support a prophylactic or protective role for apoTf, not a therapeutic effect on an existing neurodegenerative disease.
Applicant argues that Ross does not teach treatment of neurodegenerative diseases by inducing or promoting growth of new neuronal cells, but instead relates to modulation of HIF signaling and neuroprotective effects associated with ischemia, hypoxia, oxygen deprivation, or related pathological conditions. Applicant further argues that references to neurodegenerative diseases in Ross merely provide contextual background and or not therapeutic targets of the disclosed methods. Applicant additionally contends that Ross teaches prophylactic or protective administration prior to neuronal death rather than regeneration of new neural cells after neuronal loss. Applicants arguments have been fully considered but are not found persuasive.
Ross expressly teaches administration of apo transferrin for treatment of neurological and neurodegenerative conditions including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ischemia and cerebral artery occlusion. Such conditions fall within Applicant’s own definition of a “neurodegenerative event”, namely events involving loss of neural cell structure and or function and neuronal death. Therefore, Ross teaches the same patient population recited in the pending claims.
Applicant’s argument improperly attempts to distinguish the prior art based on mechanistic differences not positively recited in the claims. The pending claims do not require any particular molecular mechanism, signaling pathway, histological assay, stem cell origin or proof of de novo neuron formation. Rather, the claims broadly recite administering transferrin or lactoferrin to promote generation of neural cells or stimulate neural cell development in a patient having suffered a neurodegenerative event.
Ross teaches administration of the same therapeutic agent, apo transferrin, in patients and experimental models suffering neurological injury and neurodegenerative conditions. Ross further teaches beneficial neuronal effects following apo transferrin administration, including protection and restoration of neuronal cell systems. The claimed functional limitations therefore reasonably encompass the therapeutic cellular effects disclosed in Ross.
Applicant argues that neuroprotection is distinct from neurogenesis because neuroprotection occurs prior to irreversible neuronal death whereas neurogenesis occurs after neuronal loss. However, the pending claims contain no temporal limitation requiring administration only after irreversible neuronal death has occurred, nor do the claims exclude therapies that preserve surviving neurons, stimulate differentiation, or otherwise improve neural cell development following injury. Accordingly, the broad claim language reasonably readds on the therapeutic methods disclosed by Ross.
Further, Applicant’s arguments rely on narrowing interpretations drawn from the specification rather than the actual claim language. Although Applicant characterizes the invention as directed specifically to neurogenesis rather than neuroprotection, the claims themselves do not exclude neuroprotective mechanism or require directed evidence of newly formed neurons.
Applicant additionally argues that Ross merely references neurodegenerative diseases as conditions associated with HIF dysregulation rather than therapeutic targets. However, Ross expressly teaches administration of apo transferrin for treatment of such neurological conditions and demonstrates therapeutic effects in neuronal models associated with ischemic and neurodegenerative injury. The intended therapeutic pathway or scientific rationale underlying Ross does not negate the disclosure of administering apo transferrin in the claimed disease contexts.
Regarding the limitation requiring iron saturation less than about 20%, Ross teaches apo transferrin, which is understood in the art to represent the substantially iron free form of transferrin and therefore reasonably meets the claimed iron saturation limitation. Accordingly, Applicant has not persuasively distinguished the claimed invention from the disclosure of Ross, and thus the rejection under 35 U.S.C. 102 is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-4, 6-7, 22, 24-25, 27-28 are/remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 22-31, 43 of co-pending Application No. 18004233(reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of promoting and/or inducing generation of new neural cells or stimulating neural cell development in a patient that has suffered a neurodegenerative event, comprising administering a therapeutically effective amount of a protein selected from transferrin, lactoferrin, and combinations thereof (claims 1, 22) wherein the therapeutically effective amount of transferrin or lactoferrin administered to the patient has an iron saturation of less than about 20 % (claims 1, 22); wherein the protein is human transferrin (claim 3, 24);wherein the transferrin is plasma-derived or recombinant (claims 4, 25); wherein the transferrin is a domain of a fusion protein and the fusion partner is an immunoglobulin Fc domain (claim 6, 27); wherein the neurodegenerative event is caused by a neurodegenerative disease (claims 7, 28); wherein the neurodegenerative disease is selected from Parkinson’s disease, Alzheimer’s disease, mild cognitive impairment, diffuse Lewy body disease, demyelinating diseases such as multiple sclerosis, and other listed disorders (Claim 8).
Co-pending Application No. 18004233 claims “A method of promoting and/or inducing generation of new neural cells in a patient that has suffered a neurodegenerative event arising from at least one of a traumatic brain injury, a non-traumatic brain injury, a spinal cord injury, a peripheral nerve injury, or peripheral neuropathy,the method comprising administering a therapeutically effective amount of a protein selected from transferrin, lactoferrin, and combinations thereof to the patient in need thereof” (Claim 1); wherein the therapeutically effective amount of transferrin or lactoferrin administered to the patient has an iron saturation of less than about 20% (Claims 2 and 23); wherein the protein is human transferrin (claims 3, 24); wherein the transferrin is plasma- derived or recombinant (claims 4, 25); wherein the transferrin is a domain of a fusion protein, and the fusion partner is an immunoglobulin Fc domain (claims 6, 22); A method of stimulating neural cell development in a patient that has suffered a neurodegenerative event arising from at least one of a traumatic brain injury, a non- traumatic brain injury, a spinal cord injury, a peripheral nerve injury, or peripheral neuropathy, the method comprising administering a therapeutically effective amount of a protein selected from transferrin, lactoferrin, and combinations thereof to the patient in need thereof (claim 22). The patient populations of both applications overlap. Each encompass individuals who have experience neuronal loss or impairment resulting from a neurodegenerative condition or even (Stroke, TBI). Because the underlying clinical condition and therapeutic purpose are the same, the patient populations overlap in scope and are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicant argues that a terminal disclaimer was filed. However, there is no terminal disclaimer of record. Thus, the rejection is maintained.
Claims 1, 3-4, 6, 22, 24-25, 27 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 7-9, 11-13 of co-pending Application No. 18548545 (reference application) in view of Ross (EP2977056, cited previously). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of promoting and/or inducing generation of new neural cells or stimulating neural cell development in a patient that has suffered a neurodegenerative event, comprising administering a therapeutically effective amount of a protein selected from transferrin, lactoferrin, and combinations thereof (claims 1, 22) wherein the therapeutically effective amount of transferrin or lactoferrin administered to the patient has an iron saturation of less than about 20 % (claims 1, 22); wherein the protein is human transferrin (claim 3, 24);wherein the transferrin is plasma-derived or recombinant (claims 4, 25); wherein the transferrin is a domain of a fusion protein and the fusion partner is an immunoglobulin Fc domain (claim 6, 27); wherein the neurodegenerative event is caused by a neurodegenerative disease (claims 7, 28); wherein the neurodegenerative disease is selected from Parkinson’s disease, Alzheimer’s disease, mild cognitive impairment, diffuse Lewy body disease, demyelinating diseases such as multiple sclerosis, and other listed disorders (Claim 8).
Co-pending Application No. 18548545 claims a method of treating neural cell injury comprising administering transferrin or lactoferrin (see claims 1, 7-9) and wherein the injury is a stroke, encephalitis, ischemic stroke which meet the limitation of neurodegenerative event. Co-pending Application No. 18548545 is silent to human transferrin, iron free transferrin and fusion of the transferrin to Fc domain.
However, Ross teaches use of a therapeutically effective amount apo transferrin (iron free transferrin) in a mammal model of cerebral artery occlusion (MCAo, which is also considered a neurodegenerative event) (see Example 6). Ross teaches use of human apo transferrin (see paragraphs 0009, 0046). Ross teaches use of recombinant human apo transferrin or derived from human (see paragraph 0009). Ross teaches wherein the transferrin is used in a conjugate or fusion with Fc domain (see paragraph 0017 and claim 4) to extend the half-life of the protein. The goal of Ross is to protect neurons from injury including stroke via use of apo transferrin. It would have been obvious before the effective filing date of the claimed invention to use human Apo-transferrin for treatment of neural cell injury with cerebral ischemia and stroke. One of ordinary skill in the art would have been motivated to do so given that Ross teaches the Apo-transferrin formulation are effective to protect neurons and fusion to Fc would increase the half-life, both of which would be beneficial in the patients of Co-pending AN18548545.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicants argue that the features added by claim 1 are not found in the co-pending application and the features characterize the pending claims over the teachings of Ross. Thus, the rejection should be withdrawn.
Applicant’s arguments have been fully considered but not found persuasive. Ross teaches use of a therapeutically effective amount apo transferrin (iron free transferrin, thus meeting the newly added limitations of having an iron saturation of less than about 20%) in a mammal model of cerebral artery occlusion (MCAo, which is also considered a neurodegenerative event) (see Example 6). Ross teaches use of human apo transferrin (see paragraphs 0009, 0046). Ross teaches use of recombinant human apo transferrin or derived from human (see paragraph 0009). Ross teaches wherein the transferrin is used in a conjugate or fusion with Fc domain (see paragraph 0017 and claim 4) to extend the half-life of the protein. The goal of Ross is to protect neurons from injury including stroke via use of apo transferrin. It would have been obvious before the effective filing date of the claimed invention to use human Apo-transferrin for treatment of neural cell injury with cerebral ischemia and stroke. One of ordinary skill in the art would have been motivated to do so given that Ross teaches the Apo-transferrin formulation are effective to protect neurons and fusion to Fc would increase the half-life, both of which would be beneficial in the patients of Co-pending AN18548545. Thus, the rejection is maintained.
Claims 1, 3-4, 6-8, 22, 24-25, 27-28 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of USRE49129E1 (reference patent) in view of Ross (EP2977056, cited previously). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of promoting and/or inducing generation of new neural cells or stimulating neural cell development in a patient that has suffered a neurodegenerative event, comprising administering a therapeutically effective amount of a protein selected from transferrin, lactoferrin, and combinations thereof (claims 1, 22); wherein the therapeutically effective amount of transferrin or lactoferrin administered to the patient has an iron saturation of less than about 20 % (claims 2, 23); wherein the protein is human transferrin (claim 3, 24);wherein the transferrin is plasma-derived or recombinant (claims 4, 25); wherein the transferrin is a domain of a fusion protein and the fusion partner is an immunoglobulin Fc domain (claim 6, 27); wherein the neurodegenerative event is caused by a neurodegenerative disease (claims 7, 28); wherein the neurodegenerative disease is selected from Parkinson’s disease, Alzheimer’s disease, mild cognitive impairment, diffuse Lewy body disease, demyelinating diseases such as multiple sclerosis, and other listed disorders (Claim 8).
USRE49129E1 claims “A method of treating a Hypoxia Inducible Factor (HIF)-related pathological condition in a patient in need thereof, wherein the HIF-related pathological condition is Middle Cerebral Artery occlusion (MCAo), comprising administering to the patient a composition comprising a therapeutically effective amount of transferrin, and wherein the transferrin is a mixture of apo-transferrin and holo-transferrin in a ratio from 99% Apo-Tf:1% Holo-Tf to 30% Apo-Tf:70% Holo-Tf” (see claim1). USRE49129E1 claims wherein the transferrin is modified by pegylation, glycosylation or polysialylation to extend its plasma half-life; “A method of treating a Hypoxia Inducible Factor (HIF)-related pathological condition in a patient in need thereof, wherein the HIF-related pathological condition is a neurodegenerative disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amylotrophic Lateral Sclerosis, comprising administering to the patient a composition comprising a therapeutically effective amount of transferrin, and wherein the transferrin is a mixture of apo-transferrin (Apo-Tf, which is iron free) and holo-transferrin (Holo-Tf) in a ratio from 99% Apo-Tf:1% Holo-Tf to 30% Apo-Tf:70% Holo-Tf” (Claim 14); wherein the neurodegenerative disease is Parkinson's disease (Claim 15); wherein the transferrin is recombinant (see claim 21). USRE49129E1 is silent to treating Parkinson’s disease and fusion to Fc.
However, Ross teaches use of a therapeutically effective amount apo transferrin (iron free transferrin) in a mammal model of cerebral artery occlusion (MCAo, which is also considered a neurodegenerative event) (see Example 6) and also for treatment of Parkinson’s disease (see claim 1). Ross teaches use of human apo transferrin (see paragraphs 0009, 0046). Ross teaches use of recombinant human apo transferrin or derived from human (see paragraph 0009). Ross teaches wherein the transferrin is used in a conjugate or fusion with Fc domain (see paragraph 0017 and claim 4) to extend the half-life of the protein. The goal of Ross is to protect neurons from injury including stroke and neurodegenerative diseases via use of apo transferrin. It would have been obvious before the effective filing date of the claimed invention to use human Apo-transferrin for treatment of neural cell injury with cerebral ischemia, stroke and neurodegenerative diseases such as Parkinson’s. One of ordinary skill in the art would have been motivated to do so given that Ross teaches the Apo-transferrin formulation are effective to protect neurons and fusion to Fc would increase the half-life, both of which would be beneficial in the patients of RE. USRE49129E1 in view of Ross teaches administration of the same therapeutic agent to the same patient population under the same conditions. Therefore, any inherent neural cell developmental effects (as found in the instant claim preamble) resulting from administration of apo transferrin to the same patient population would reasonably occur upon practicing the prior art methods.
Response to Applicant’s Arguments
Applicant argues The claims of USRE49129E1 relate to "a method of treating a Hypoxia Inducible Factor (HIF)-related pathological condition in a patient in need thereof, wherein the HIF-related pathological condition is Middle Cerebral Artery occlusion (MCAo), comprising administering to the patient a composition comprising a therapeutically effective amount of transferrin, and wherein the transferrin is a mixture of apo-transferrin and holo-transferrin in a ratio from 99% Apo-Tf:1% Holo-Tf to 30% Apo-Tf:70% Holo-Tf". The claimed invention of USRE49129E1 relates to treating neurodegenerative diseases via a different mechanism (not inducing new neural cells), the mechanism being modulation of HIF signaling in pathological condition such as Middle Cerebral Artery occlusion (MCAo). Thus, the presently claimed invention can be patentably distinguished from the claims of USRE49129E1. Moreover, Claim 1 has been amended as stated above. The amendment to Claim 1 are not found in Claims 1-22 of USRE49129E1, and these amendments characterize over the disclosure or Ross.
Applicant’s arguments have been fully considered but not found persuasive. As stated previously, USRE449129 E1 expressly teaches treatment of neurodegenerative disease including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and MCAo, through administration of transferrin compositions. Ross teaches use of apo transferrin in neurological injury and neurodegenerative disease contexts including Parkinson’s and cerebral ischemia. Applicant’s attempt to distinguish neuroprotection from neurogenesis relies on limitations not positively recited in the claims. The claims do not exclude neuroprotective mechanisms of HIF mediated effects. USRE49129E1 in view of Ross teaches administration of the same therapeutic agent to the same patient population under the same conditions. Therefore, any inherent neural cell developmental effects resulting from administration of apo transferrin to the same patient population would reasonably occur upon practicing the prior art methods.
New Rejection
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-4, 6, 22, 24-25, 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of US Patent No. 9687530 (reference patent) in view of Ross (EP2977056, cited previously). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of promoting and/or inducing generation of new neural cells or stimulating neural cell development in a patient that has suffered a neurodegenerative event, comprising administering a therapeutically effective amount of a protein selected from transferrin, lactoferrin, and combinations thereof (claims 1, 22); wherein the therapeutically effective amount of transferrin or lactoferrin administered to the patient has an iron saturation of less than about 20 % (claims 2, 23); wherein the protein is human transferrin (claim 3, 24);wherein the transferrin is plasma-derived or recombinant (claims 4, 25); wherein the transferrin is a domain of a fusion protein and the fusion partner is an immunoglobulin Fc domain (claim 6, 27); wherein the neurodegenerative event is caused by a neurodegenerative disease (claims 7, 28); wherein the neurodegenerative disease is selected from Parkinson’s disease, Alzheimer’s disease, mild cognitive impairment, diffuse Lewy body disease, demyelinating diseases such as multiple sclerosis, and other listed disorders (Claim 8).
US Patent No. 9687530 claims “A method of treating a Hypoxia Inducible Factor (HIF)-related pathological condition in a patient in need thereof, wherein the HIF-related pathological condition is Middle Cerebral Artery occlusion (MCAo) which is considered a neurodegenerative event, comprising administering to the patient a composition comprising a therapeutically effective amount of transferrin, and wherein the transferrin is a mixture of apo-transferrin and holo-transferrin in a ratio from 99% Apo-Tf:1% Holo-Tf to 30% Apo-Tf:70% Holo-Tf.(see claim 1). US Patent No. 9687530 claims wherein the transferrin is recombinant (see claim 11) and modified for half life (see claim 12). US Patent No. 9687530 is silent to fusion to Fc.
However, Ross teaches use of a therapeutically effective amount apo transferrin (iron free transferrin) in a mammal model of cerebral artery occlusion (MCAo, which is also considered a neurodegenerative event) (see Example 6). Ross teaches use of recombinant human apo transferrin or derived from human (see paragraph 0009). Ross teaches wherein the transferrin is used in a conjugate or fusion with Fc domain (see paragraph 0017 and claim 4) to extend the half-life of the protein. The goal of Ross is to protect neurons from injury including stroke via use of apo transferrin. It would have been obvious before the effective filing date of the claimed invention to use human Apo-transferrin for treatment of neural cell injury with cerebral ischemia and stroke. One of ordinary skill in the art would have been motivated to do so given that Ross teaches the Apo-transferrin formulation are effective to protect neurons and fusion to Fc would increase the half-life, both of which would be beneficial in the patients of US Patent No. 9687530. US9687530 in view of Ross teaches administration of the same therapeutic agent to the same patient population under the same conditions. Therefore, any inherent neural cell developmental effects (as found in the instant claim preamble) resulting from administration of apo transferrin to the same patient population would reasonably occur upon practicing the prior art methods.
Claims 1, 3-4, 6, 22, 24-25, 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-42 of Co-pending 18/993489 in view of Ross (EP2977056, cited previously). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of promoting and/or inducing generation of new neural cells or stimulating neural cell development in a patient that has suffered a neurodegenerative event, comprising administering a therapeutically effective amount of a protein selected from transferrin, lactoferrin, and combinations thereof (claims 1, 22); wherein the therapeutically effective amount of transferrin or lactoferrin administered to the patient has an iron saturation of less than about 20 % (claims 2, 23); wherein the protein is human transferrin (claim 3, 24);wherein the transferrin is plasma-derived or recombinant (claims 4, 25); wherein the transferrin is a domain of a fusion protein and the fusion partner is an immunoglobulin Fc domain (claim 6, 27); wherein the neurodegenerative event is caused by a neurodegenerative disease (claims 7, 28); wherein the neurodegenerative disease is selected from Parkinson’s disease, Alzheimer’s disease, mild cognitive impairment, diffuse Lewy body disease, demyelinating diseases such as multiple sclerosis, and other listed disorders (Claim 8).
Co-pending 18/993489 claims A method of treating stroke (a neurodegenerative event as defined by Applicant) comprising administering antithrombin (claim 23). Co-pending 18/993489 further claims administering with transferrin with a iron saturation of less than 30% (see claims 40-41). Co-pending 18/993489 is silent to iron saturation less than 20% (i.e. apo transferrin) and fusion to Fc.
However, Ross teaches use of a therapeutically effective amount apo transferrin (iron free transferrin) in a mammal model of cerebral artery occlusion and stroke (MCAo, Stroke, which is also considered a neurodegenerative event) (see Example 6, see paragraph 0022). Ross teaches use of recombinant human apo transferrin or derived from human (see paragraph 0009). Ross teaches wherein the transferrin is used in a conjugate or fusion with Fc domain (see paragraph 0017 and claim 4) to extend the half-life of the protein. The goal of Ross is to protect neurons from injury including stroke via use of apo transferrin. It would have been obvious before the effective filing date of the claimed invention to use human Apo-transferrin for treatment of neural cell injury with cerebral ischemia and stroke. One of ordinary skill in the art would have been motivated to do so given that Ross teaches the Apo-transferrin formulation are effective to protect neurons and fusion to Fc would increase the half-life, both of which would be beneficial in the patients of Co-pending 18/993489. Co-pending 18/993489 in view of Ross teaches administration of the same therapeutic agent to the same patient population under the same conditions. Therefore, any inherent neural cell developmental effects (as found in the instant claim preamble) resulting from administration of apo transferrin to the same patient population would reasonably occur upon practicing the prior art methods.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 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, Lianko Garyu can be reached at 571-270-7367. 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.
/ERINNE R DABKOWSKI/Examiner, Art Unit 1654
Prosecution Insights