DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to a claim set filed 6/20/2024 and response filed 8/5/2026.
Claims 1-16 are pending.
This application claims priority to U.S. provisional application 63/509,033 filed 6/20/2023.
Election/Restrictions
Applicants’ election with traverse of Group I (Claims 1-9 and 12-16, drawn to a hypoventilation physical model comprising a brainstem organoid and a cerebral organoid formed from PSC with a PHOX2B mutation and system comprising) in the reply filed on 8/5/2026 is acknowledged. The traversal is on the ground(s) that the claims represent overlapping search matter. This is not found persuasive because this is not the standard to determine independent inventions. Rather, the inventions must be assessed as to search burden established by the following criteria.
(A) Separate classification thereof: This shows that each invention has attained recognition in the art as a separate subject for inventive effort, and also a separate field of search. Patents need not be cited to show separate classification.
(B) A separate status in the art when they are classifiable together: Even though they are classified together, each invention can be shown to have formed a separate subject for inventive effort when the examiner can show a recognition of separate inventive effort by inventors. Separate status in the art may be shown by citing patents which are evidence of such separate status, and also of a separate field of search.
(C) A different field of search: Where it is necessary to search for one of the inventions in a manner that is not likely to result in finding art pertinent to the other invention(s) (e.g., searching different classes/subclasses or electronic resources, or employing different search queries, a different field of search is shown, even though the two are classified together. The indicated different field of search must in fact be pertinent to the type of subject matter covered by the claims. Patents need not be cited to show different fields of search. (see MPEP § 808.02).
The claims have been found to represent a search burden. The requirement is still deemed proper and is therefore made FINAL.
Claims 10 and 11 are withdrawn from examination as being directed to non-elected subject matter.
Information Disclosure Statement
An IDS filed 8/19/2024 has been identified and the documents considered. The signed and initialed PTO Form 1449 has been mailed with this action. In the case that the English abstract alone was identified, this is indicated.
Specification
The disclosure is objected to because of the following informalities: the word “model” is misspelled in ¶0024 as modul. .Appropriate correction is required.
Sequence Compliance
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below or on the attached Notice To Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures.
Specifically, Figure 5A, 8B and 10 contain sequences that are not identified by sequence identifier numbers. If the sequences can be found in the sequence listing it would be remedial to insert the appropriate SEQ ID NO:s. If not, a substitute paper copy of the “Sequence Listing”, as well as an amendment directing its entry into the specification, CRF and letter stating that the contents of the sequence listing and the CRF are the same and contain no new matter is required. The nature of the non-compliance did not preclude the examination on the merits of the instant application, the results of which follow.
Drawings
Figures 1C (far left figure) and 15B are objected to under 37 CFR 1.83(a) because they fail to show any details as described in the specification. Specifically, the figures contain text that is not legible. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). A proposed drawing correction or corrected drawings are required in reply to the Office action to avoid abandonment of the application. The objection to the drawings will not be held in abeyance.
Applicants petition to accept color photographs has been granted on 8/8/2024.
Claim Objections
Claims 1, 4 and 5 are objected to because of the following informalities: claim 1 is grammatically incorrect and should recite --each of the brainstem organoid and the cerebral organoid are” as well they are not “formed by” but are --generated from pluripotent stem cells--.
Claim 4 contains grammatical inaccuracy by reciting that “the PARM is happened on” which should be --is located on--.
In claim 5, line 4, the preposition “to” should be –into--. As well, SHH, WNT, BDNF, GDNF are provided as abbreviation and should be spelled out in full. In line 10, the article “the” is required prior to “TGF-b". As well, “for incubation and collecting matured brainstem organoids” should be --followed by culturing the cells in the third culture medium to form mature brainstem organoids-- to be complete.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 5, 6 and 13-15 are rejected 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.
Claim 5 recites the limitation "the medium" in line 12. There is insufficient antecedent basis for this limitation in the claim. There is a “first culture medium” and a “second culture medium” and the claim does not distinguish to which the reference is being made. Given the lack of order of the steps, this is true of all reference to “the medium” in the claim.
The recitation in claim 5 of “the second culture medium supplemented with the SHH agonist, a WNT agonist and retinoic acid” is unclear. It is unclear what is actually part of the media. As the second medium has an SHH agonist, it is unclear if this is a distinct second medium from that previously recited. This is complicated by reference to “the medium” wherein this could be a parallel step to that of the previously recited change to second medium.
Claim 6 is unclear for reciting that “the PSCs” in line 3 are transferred to a low attachment plate. The organoid is formed from PSCs that are suspended in line 3 to form single cell suspensions. Hence, it is not clear if it is the single cell suspensions that are transferred or the originating PSCs.
Claim 6 recites in multiple places “the embryoid bodies” wherein the multiple recitations do not distinguish to which the claims are referencing. Hence there is a lack of adequate antecedent basis for this limitation throughout the claims. In fact, in line 10, neuroepithelia are formed and yet the next line recites embedding the embryoid bodies in a basement membrane. Hence, it is further unclear what happens to the neuroepithelia. The claim also recites in line 13, “the medium” which does not indicate to which medium the step requires. Hence, this limitation lacks proper antecedent basis.
Claim 13 recites “the PHOX2B gene mutation” in claim 12. There is insufficient antecedent basis for this limitation in the claim. This is true of claim 14.
Claims 13 and 16 are unclear as it is not clear if the claim is drawn to the product (hypoventilation physical models) or process (mutation is corrected and hENCCS are differentiated). A claim cannot refer to both a product and a process unless it is clearly drafted as a product by process (MPEP 2173.05(p)).
Claim 15 is vague and indefinite in that the metes and bounds of the term “derived from” are unclear. It is unclear the nature and number of steps required to obtain a “derivative” of hENCCs. The term implies a number of different steps that may or may not result in a change in the functional characteristics of the neurons from the source that it is “derived from”.
MPEP 2173 Clear Notice Requirement “Optimizing patent quality by providing clear notice to the public of the boundaries of the inventive subject matter protected by a patent grant ... “’“ ... to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent.”
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.
Claims 1-9 and 12-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is drawn to use of PSC cells to form brainstem organoids (HSBOs) and cerebral organoids (HCOs) to form the hypoventilation physical model. This model is used for “studying impaired ventilatory responses and associated neuronal defects, offering a valuable tool for drug screening and the development of therapeutic strategies for hypoventilation syndromes (abstract)”. As to the gene mutation the disclosure teaches only 5-PARM, 7-PARM, and 13-PARM. These mutations occur within a 20-alanine polyalanine tract in exon 3 of the PHOX2B gene.
[0005] The longer polyalanine repetitions are associated with aberrant cytoplasmic retention of PHOX2B, which adversely affects its transcriptional activity and its binding to the promoter of the dopamine beta-hydroxylase (DBH) gene. Thus, the length of PARMs in PHOX2B is closely related to the clinical phenotypes and disease severity observed in patients.
[0062] However, the combination of these two types of organoids is required in order to adequately replicate human physiological and genetic conditions associated with hypoventilation syndromes. A hypoventilation physical model according to the present invention includes both brainstem organoids and cerebral organoids, both derived from pluripotent stem cells (PSCs) containing a specific mutation in the PHOX2B gene. The PHOX2B gene mutation of interest includes polyalanine repeat expansion mutations (PARMs), particularly 5-PARM, 7-PARM, and 13-PARM. These mutations occur within a 20-alanine polyalanine tract in exon 3 of the PHOX2B gene.
These mutations are established throughout the disclosure as critical for formation of a hypoventilation model. Claim 1 is incomplete by reciting only a gene mutation. This aspect is also lacking in claim 12. Claim 12 is drawn to a hypoventilation model simply described as comprising a brainstem organoid and a cerebral organoid wherein the brainstem organoid includes PHOX2B neurons with reduced DBH expression. These properties are distinctly provided by those mutations.
[0130] PHOX2B-PARMs (PHOX2B-5Ala, PHOX2B-7Ala, and PHOX2B-13Ala) alone do not affect hENCC yield nor their subsequent neuronal differentiation to make PHOX2B+ neurons (FIGS. 8I and 8K), including TH.sup.+ (FIGS. 8J and 8M) ENS neurons, but they deter the formation of dopamine beta-hydroxylase (DBH) neurons where DBH is the direct target of PHOX2B (FIGS. 8I and 8L).
Hence, the PHOX2B mutation while not claimed appears embraced by the claim. The only structure that will meet the function recited in claim 12 is a brainstem comprising PHOX2B-PARMs (PHOX2B-5Ala, PHOX2B-7Ala, and PHOX2B-13Ala mutations.
Secondly, the brainstem and cerebral organoids each have functional properties as recited in claims 7 and 8 wherein (claim 7) the brainstem organoid comprises retrotrapezoid nucleus (RTN) neurons and exhibits increased firing in response to elevated CO2 levels and (claim 8) the cerebral organoid comprises functional neurons expressing glutamatergic, GABAergic, cholinergic, and serotonergic markers. These components are necessary and inherent components of the recited physical model system. Rather, claims 7 and 8 are inherent properties of the cells required for the model of claim 1. The structures are not altered by reciting the functional requirements.
Thirdly, claim 9 drawn broadly to “a neuronal differentiation medium optimized” to produce ENS neurons from hENCCs wherein this media is described in the disclosure with a single example as the following.
[0083] Neuronal differentiation of hENCCs to ENS neurons is initiated by replacing the medium with N2 medium supplemented with 10 ng ml.sup.−1 BDNF, 10 ng ml.sup.−1 GDNF, 10 ng ml.sup.−1 NT-3 and 10 ng ml.sup.−1 β-NGF, 1 μM dibutyryl-cAMP and 200 μM ascorbic acid. The cells are cultured in the neuronal differentiation medium up to 20 days and the medium was changed every 2-3 days.
This means that the organoids require specific media as the single example dictates that this media is specific to the goal. One could not envision an optimized neuronal medium with the organoids as claimed that must produce ENS except the singular disclosure. This means, claim 16, drawn to the hypoventilation model wherein the hENCCS are further differentiated to express PHOX2B and have ENS defects are actually ENS neurons. The claim is recited as a product with a process step. If it is intended that the claim is a product by process claim, it must be re-formatted as such. Finally, in claim 13 the recitation that the PHOS2B mutation is corrected appears to embrace a product by process claim which would require that the verb be in the past. The claim is a product and cannot involve a process as well unless it is a product by process claim. However, to do so would make a product different than the one from which the claim refers and it is not clear that this would still be a hypoventilation model as described in the disclosure as the mutation is explicitly connected with the model.
The claims as set forth above rely on generic language as well as functional language with limited descriptive elements such that the claims broadly and incompletely claim the inventive elements. The written description requirement for genus claims may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with known or disclosed correlations between function and structure, or by a combination of such characteristics sufficient to show that the applicant was in possession of the claimed genus.
To this end, the MPEP provides such guidance (emphasis added). If the application as filed does not disclose the complete structure (or acts of a process) of the claimed invention as a whole, determine whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. For example, if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Compare Fonar, 107 F.3d at 1549, 41 USPQ2d at 1805 (disclosure of software function adequate in that art).
Conclusion
The invention was not found in the art. Applicants’ publication dated 6/22/2023 as to availability alone teaches the invention.
Lui et al, Organoid models of breathing disorders reveal patterning defect of hindbrain neurons caused by PHOX2B-PARMs, Stem Cell Reports, 2023, 1500–1515.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIA MARVICH whose telephone number is (571)272-0774. The examiner can normally be reached 8 am - 5 pm.
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/MARIA MARVICH/Primary Examiner, Art Unit 1634
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