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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 13, 2026 has been entered.
Detailed Action
This action is in response to the papers filed April 13, 2026.
Amendments
Applicant's amendments, filed April 13, 2026, is acknowledged. Applicant has cancelled Claims 1-10, 12-32, 34-35, 38-39, 41-46, 48, 50-64, 66, and 68-73, amended Claims 11, 33, 36, 37, 40, 49, 65, and 74-76, withdrawn Claims 11, 47, 67, and 74, and added new claims, Claims 77-81.
Claims 11, 33, 36-37, 40, 47, 49, 65, 67, and 74-81 are pending.
The amendment to the claims filed on April 13, 2026 does not comply with the requirements of 37 CFR 1.121(c) and 37 CFR 1.126.
Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
(2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of "currently amended," and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of "currently amended," or "withdrawn" if also being amended, shall include markings.
The correct status of Claim 40 is (Withdrawn, currently amended).
Claims 11, 33, 36-37, 40, 47, 49, 65, 67, and 74-81 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group I, Claims 1-2, 6, 11, 33, 36-37, 40-41, 44, 47, 49, 56, 61, 63-65, 67, and 74-75, drawn to a method for delivering a complex of two or more molecules into an immune cell, the method comprising the step(s) of:
i) passing a cell suspension comprising immune cells through a constriction, classified in CPC C12N 15/87.
Within Group I, Applicant has elected without traverse the following species, wherein:
i) the alternative molecule present in the complex is “one or more polypeptides”, as recited in Claims 36(a);
ii) the alternative complex formation context is “the complex is formed prior to the contacting”, as recited in Claim 44;
iii) the alternative immune cell is a “T cell”, as recited in Claim 75;
iv) the alternative contacting is “before the cell suspension passes through the constriction”, as recited in Claim 41;
v) the alternative contacting condition is “at a temperature ranging from about 0C to about 40C”, as recited in Claim 11; and
vi) the alternative complex functional property is “has a half-life in the cell suspension of about 1 minute to about 48 hours”, as recited in Claim 6.
Claims 11, 33, 36-37, 40, 47, 49, 65, 67, and 74-81 are pending.
Claims 11, 40, 47, 67, and 74 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Newly submitted Claim 79 is directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: the claim is directed to alternative additional method steps and/or alternative functional properties.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, Claim 79 is withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claims 33, 36-37, 49, 65, 75-78, and 80-81 are under consideration.
Priority
This application is a continuation of application 16/068,631 filed on July 6, 2018, now abandoned, which is a 371 of PCT/US2017/013055 filed on January 11, 2017. Applicant’s claim for the benefit of a prior-filed application provisional application 62/277,858 filed on January 12, 2016 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed application, Application No. 62/277,858 filed on January 12, 2016 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Claims 77-78 and 80 recite a method for delivering a complex of two or more molecules into a cell, the method comprising the steps of:
a) forming a complex of two or more molecules,
wherein the two or more molecules of the complex are associated by a noncovalent interaction, and
wherein the complex comprises at least one polypeptide;
b) contacting a cell suspension comprising cells with the complex of two or more molecules at a temperature of about 20 °C; and
c) passing the cell suspension and the complex through a constriction at a temperature of about 20 °C,
wherein the cell suspension comprises a viscosity ranging between about 0.89 cP and about 2.0 cP as measured at about 20 °C,
wherein the constriction comprises a width in the smallest dimension of about 3 μm to about 8 μm.
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
Original disclosure may not be relied upon unless it “constitute[s] a full, clear, concise and exact description” of the invention claimed in the patent to one of ordinary skill. In re Wertheim, 646 F.2d 527, 538–39 (CCPA 1981).
For genus claims, which are present here, we have looked for blaze marks within the disclosure that guide attention to the claimed species or subgenus. In re Ruschig, 379 F.2d 990, 994–95 (CCPA 1967); Fujikawa v. Wattana-sin, 93 F.3d 1559, 1571 (Fed. Cir. 1996); see also Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326–27 (Fed. Cir. 2000).
Following this maze-like path, each step providing multiple alternative paths, is not a written description of what might have been described if each of the optional steps had been set forth as the only option. This argument calls to mind what Yogi Berra, the Yankee catcher, was reported to have said: “when one comes to a fork in the road, take it.” That comment was notable because of its indeterminacy, its lack of direction. Similarly, here, all those optional choices do not define the intended result of the instant combination of specific method step parameters.
Clearly, however, just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety. Were this the case, a “laundry list” disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not “reasonably lead” those skilled in the art to any particular species.
Indeed, the listings of possibilities are so long, and so interwoven, that it is quite unclear how many compounds actually fall within the described genera and subgenera.
As explained by the Board, “[t]hese blaze marks must be clear because ‘it is easy to bypass a tree in the forest, even one that lies close to the trail.’” Decision at *10 (citing Fujikawa, 93 F.3d at 1571).
The Board concluded that, “[i]n this case, we find the point at which one must leave the trail to find the tree is not well marked in [provisional application]. Thus, [provisional application] do not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
In the instant case, 62/277,858 recites a plurality of interwoven claims directed to individual parameter ranges, e.g. a temperature between 0C to 4C (claim 11), constriction width of 0.4um to 14um (claim 61), shear forces between 1kPa and 100kPa (claims 33-35), binding affinities between 1uM to 1pM (claims 4-5), ionic strengths between 50mM to 1000mM (claims 15-18), buffer/medium osmolarity values between 0 to 1000 mOsm/L (claims 24-25, 27-28), buffer/medium pH values ranging from 4.0 to 10.0 (claims 29-32). However, the originally filed claims, being so interwoven, do not provide sufficient blazemarks nor reasonably lead the ordinary artisan to the instantly recited combination of experimental parameters.
62/277,858 Examples 1-2 fail to disclose the combination of the method step parameters of a physiological saline solution or cell culture medium having a viscosity of about 0.89-2.0 cP, and passing the immune cells through a constriction width of about 3-8um. At best, it merely discloses the microfluidic channel has a constriction width of 4um and a channel length of 10 or 30 um. Instant Claim 1 is far broader in scope than 62/277,858 Examples 1-2.
The working examples fail to disclose the temperature, nor viscosity of the buffer/medium.
Applicant appears to be cherry-picking disparate, unconnected, method step parameter subgenera, and combinations and/or subcombinations thereof, which are not supported by the originally filed disclosure.
PCT/US2017/013055 filed on January 11, 2017 and 16/068,631 filed on July 6, 2018, having the same specification as 62/277,858 suffer the same deficiencies.
See further discussion below under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection.
Accordingly, the effective priority date of the instant application is granted as August 29, 2022, the effective filing date of the instant application.
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
Response to Arguments
Applicant argues that the abstract, paragraphs [0001, 4, 12, 54, 70-76, 79, and 97-102], Examples 1-2, and claims 1, 3, and 42 of 62/277,858 provide clear and sufficient support for new Claims 77, 78 and 80.
Applicant’s argument(s) has been fully considered, but is not persuasive.
The abstract of 62/277,858 is silent to the instantly recited method step parameter(s), and combinations and/or subcombinations thereof.
[0001, 4, 12, 54, 70-74, 76, 79, 97-98, and 100-102] of 62/277,858 is/are silent to the instantly recited method step parameter(s), and combinations and/or subcombinations thereof.
While [0075] discloses a viscosity ranging between about 0.89 cP and about 2.0 cP, whereby said viscosity may be measured at any temperature between about 0 °C and about 40 °C. There is/are no blazemarks that immediately lead to instantly recited “about 20 °C”, nor instantly recited combination of method step parameters.
While [0099] discloses the method may be performed at a temperature ranging between about between about -5 °C and about 45 °C. There is/are no blazemarks that immediately lead to instantly recited “about 20 °C”, nor instantly recited combination of method step parameters.
Claims 1, 3, and 42 of 62/277,858 is/are silent to the instantly recited method step parameter(s), and combinations and/or subcombinations thereof.
Example 1 of 62/277,858 is silent to the instantly recited combination of method step parameters:
b) contacting a cell suspension comprising cells with the complex of two or more molecules at a temperature of about 20 °C; and
c) passing the cell suspension and the complex through a constriction at a temperature of about 20 °C,
wherein the cell suspension comprises a viscosity ranging between about 0.89 cP and about 2.0 cP as measured at about 20 °C,
wherein the constriction comprises a width in the smallest dimension of about 3 μm to about 8 μm.
At best, Example 1 [0182] discloses the constriction length is the same as the width, to wit, 4 μm.
Example 2 of 62/277,858 is silent to the instantly recited combination of method step parameters:
b) contacting a cell suspension comprising cells with the complex of two or more molecules at a temperature of about 20 °C; and
c) passing the cell suspension and the complex through a constriction at a temperature of about 20 °C,
wherein the cell suspension comprises a viscosity ranging between about 0.89 cP and about 2.0 cP as measured at about 20 °C,
wherein the constriction comprises a width in the smallest dimension of about 3 μm to about 8 μm.
At best, Example 2 [0185] discloses the constriction length is 10 or 30 μm, and the width is 4 μm.
Instant independent claims are broader in scope than ‘858 disclosure of the constriction width of 4 μm.
Applicant fails to point with particularity by page and line number where in the specifications of 62/277,858, PCT/US2017/013055, and instant application support for the combination of instantly recited method step parameters is found.
Applicant appears to be cherry-picking disparate, unconnected, method step parameter subgenera, and combinations and/or subcombinations thereof, which are not supported by the originally filed disclosure.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on April 13, 2026 that has been considered.
The information disclosure statement filed April 13, 2026 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Claim Objections
1. Claims 77-78 and 80 are objected to because of the following informalities:
Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
The claims recite a multitude of ‘wherein’ clauses, each of which should be separated from by line indentation.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
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.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
2. Claims 33, 36-37, 49, 65, and 75-76 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The claims recite dependency upon a later claim, Claim 77, and thus does not comply with 35 U.S.C. 112(d).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Applicant should correct the numbering of the entire claim set to a priori comply with 35 U.S.C. 112(d).
Appropriate correction is required.
Absent objective evidence to the contrary, such an amendment to the claim set, as a whole, to comply with presentation of correct claim numbering and correct claim dependency in accordance with the requirements of 35 U.S.C. 112(d) is considered remedial.
See, for example, Claim 79, dependent upon Claim 78.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
3. Claims 33, 36-37, 49, 65, 75-77, and 80-81 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.
Claims 77 and 80 recite the limitation “the immune cell” (last ‘wherein’ clause). There is insufficient antecedent basis for this limitation in the claims.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the deficiencies of the independent claims.
4. Claim(s) 81 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 80 recites a method for delivering a complex of two or more molecules into a cell, the method comprising:
a) forming a complex of two or more molecules;
b) contacting a cell suspension comprising cells with the complex; and
c) passing the cell suspension and the complex through a constriction,
wherein steps a)-c) result in higher levels of delivery of one or more molecules of the complex into the immune cell as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a).
Claim 81 recites wherein the complex is delivered to less than 25% of the cells when the cell suspension is passed through the constriction in accordance with step a) and contacted in accordance with step b) except that one or more of the two or more molecules are not pre-formed in the complex.
Either this is an inherent property of (that naturally flows from) the method step parameters of Claim 80, or it is not, and something of the method step(s) of Claim 80 must change.
To the extent it is an inherent property of (that naturally flows from) the product/method of the independent claim, then the instant claim fails to further limit the independent claim.
Furthermore, in regard to instant claims, it is noted that the “wherein…” clause does not recite any additional structure(s) and/or active method step(s), but simply states a characterization or conclusion of the results of positively recited in Claim 80. Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
The claims fail to recite, and the specification fails to disclose, the structure/function nexus and/or method step/function nexus that does not yield the functional limitations of Claim 81, as opposed to the structure/function nexus and/or method step/function nexus that does yield the functional limitations of Claim 81.
The claims fail to recite, and the specification fails to disclose, a method of Claim 80 that does not yield the functional limitations of Claim 81.
'Even if such a phrase did hold patentable weight, the phrase would likely be rejected under 35 USC 112(b) for being indefinite because such a phrase would amount to a 'functional limitation' whereby one of ordinary skill in the art would essentially need to 'guess' what steps must occur in the claim, in addition to the positively-recited method steps, in order to result in 'wherein the....' (the 'intended result' phrase in the claim).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
5. Claim(s) 81 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 80 recites a method for delivering a complex of two or more molecules into a cell, the method comprising:
a) forming a complex of two or more molecules;
b) contacting a cell suspension comprising cells with the complex; and
c) passing the cell suspension and the complex through a constriction,
wherein steps a)-c) result in higher levels of delivery of one or more molecules of the complex into the immune cell as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a).
Claim 81 recites wherein the complex is delivered to less than 25% of the cells when the cell suspension is passed through the constriction in accordance with step a) and contacted in accordance with step b) except that one or more of the two or more molecules are not pre-formed in the complex.
Either this is an inherent property of (that naturally flows from) the method step parameters of Claim 80, or it is not, and something of the method step(s) of Claim 80 must change.
The claim denotes that not all of the method step parameters of Claim 80 necessarily and predictably achieve the functional properties recited in Claim 81.
To the extent it is not an inherent property of (that naturally flows from) the product/method of the independent claim, then the instant claim lacks adequate written description for the structure/function nexus and/or method step(s)/function nexus in order to achieve the functional properties recited in Claim 81.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The “wherein…” clause does not recite any additional structure(s) and/or active method step(s), but simply states a characterization or conclusion of the results of positively recited in Claim 80. Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
The claims fail to recite, and the specification fails to disclose, the structure/function nexus and/or method step/function nexus that does not yield the functional limitations of Claim 81, as opposed to the structure/function nexus and/or method step/function nexus that does yield the functional limitations of Claim 81.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first structure/function nexus and/or method step/function nexus that does not yield the functional limitations of Claim 81, into a second structure/function nexus and/or method step/function nexus that now necessarily and predictably yields the functional limitations of Claim 81.
The claims fail to recite, and the specification fails to disclose, a method of Claim 80 that does not yield the functional limitations of Claim 81.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
New matter
6. Claim(s) 33, 36-37, 49, 65, 75-78, and 80-81 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 Examiner incorporates herein the above Priority discussion.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 77-78 and 80 recite a method for delivering a complex of two or more molecules into a cell, the method comprising the steps of:
a) forming a complex of two or more molecules,
wherein the two or more molecules of the complex are associated by a noncovalent interaction, and
wherein the complex comprises at least one polypeptide;
b) contacting a cell suspension comprising cells with the complex of two or more molecules at a temperature of about 20 °C; and
c) passing the cell suspension and the complex through a constriction at a temperature of about 20 °C,
wherein the cell suspension comprises a viscosity ranging between about 0.89 cP and about 2.0 cP as measured at about 20 °C,
wherein the constriction comprises a width in the smallest dimension of about 3 μm to about 8 μm.
Claim 77 recites wherein steps a)-c) result in higher levels of delivery of one or more molecules of the complex into the immune cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a).
Claim 78 recites wherein steps a)-c) result in a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a).
Claim 80 recites wherein steps a)-c) result in higher levels of delivery of one or more molecules of the complex into the immune cell as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a).
Clear support for the new limitation(s) cannot be found in the instant application or priority documents. Accordingly, the amendment(s) to Claim(s) 77-78 and 80 is/are considered to constitute new matter.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application”. MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure” (emphasis added).
Applicant argues that the abstract, paragraphs [0001, 4, 12, 54, 70-76, 79, and 97-102], Examples 1-2, and claims 1, 3, and 42 of 62/277,858 provide clear and sufficient support for new Claims 77, 78 and 80.
Applicant’s argument(s) has been fully considered, but is not persuasive.
The abstract of 62/277,858 is silent to the instantly recited method step parameter(s), and combinations and/or subcombinations thereof.
[0001, 4, 12, 54, 70-74, 76, 79, 97-98, and 100-102] of 62/277,858 is/are silent to the instantly recited method step parameter(s), and combinations and/or subcombinations thereof.
While [0075] discloses a viscosity ranging between about 0.89 cP and about 2.0 cP, whereby said viscosity may be measured at any temperature between about 0 °C and about 40 °C. There is/are no blazemarks that immediately lead to instantly recited “about 20 °C”, nor instantly recited combination of method step parameters.
While [0099] discloses the method may be performed at a temperature ranging between about between about -5 °C and about 45 °C. There is/are no blazemarks that immediately lead to instantly recited “about 20 °C”, nor instantly recited combination of method step parameters.
Claims 1, 3, and 42 of 62/277,858 is/are silent to the instantly recited combination of method step parameters.
Example 1 of 62/277,858 is silent to the instantly recited combination of method step parameters:
b) contacting a cell suspension comprising cells with the complex of two or more molecules at a temperature of about 20 °C; and
c) passing the cell suspension and the complex through a constriction at a temperature of about 20 °C,
wherein the cell suspension comprises a viscosity ranging between about 0.89 cP and about 2.0 cP as measured at about 20 °C,
wherein the constriction comprises a width in the smallest dimension of about 3 μm to about 8 μm.
At best, Example 1 [0182] discloses the constriction length is the same as the width, to wit, 4 μm.
Example 2 of 62/277,858 is silent to the instantly recited combination of method step parameters:
b) contacting a cell suspension comprising cells with the complex of two or more molecules at a temperature of about 20 °C; and
c) passing the cell suspension and the complex through a constriction at a temperature of about 20 °C,
wherein the cell suspension comprises a viscosity ranging between about 0.89 cP and about 2.0 cP as measured at about 20 °C,
wherein the constriction comprises a width in the smallest dimension of about 3 μm to about 8 μm.
At best, Example 2 [0185] discloses the constriction length is 10 or 30 μm, and the width is 4 μm.
Instant independent claims are broader in scope than ‘858 disclosure of the constriction width of 4 μm.
Instant specification Examples 1-2 suffer the same deficiencies as the ‘858 disclosure.
Instant specification Examples 3-5 are silent to a viscosity ranging between about 0.89 cP and about 2.0 cP as measured at about 20 °C, as claimed.
Applicant fails to point with particularity by page and line number where in the specifications of 62/277,858, PCT/US2017/013055, and instant application support for the combination of instantly recited method step parameters is found.
Applicant appears to be cherry-picking disparate, unconnected, method step parameter subgenera, and combinations and/or subcombinations thereof, which are not supported by the originally filed disclosure.
Alternatively, if Applicant believes that support for combination of method step parameters, as now recited in Claim(s) 77-78 and 80, is present and clearly envisaged in the instant application or earlier filed priority documents, applicant must, in responding to this Office Action, point out with particularity, where such support may be found.
Declarations and new references cannot demonstrate possession of a concept after the fact.
Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence.
7. Claims 33, 36-37, 49, 65, 75-78, and 80-81 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.
Claims 77-78 and 80 recite a method for delivering a complex of two or more molecules into a cell, the method comprising the steps of:
a) forming a complex of two or more molecules,
wherein the two or more molecules of the complex are associated by a noncovalent interaction, and
wherein the complex comprises at least one polypeptide;
b) contacting a cell suspension comprising cells with the complex of two or more molecules at a temperature of about 20 °C; and
c) passing the cell suspension and the complex through a constriction at a temperature of about 20 °C,
wherein the cell suspension comprises a viscosity ranging between about 0.89 cP and about 2.0 cP as measured at about 20 °C,
wherein the constriction comprises a width in the smallest dimension of about 3 μm to about 8 μm.
Claim 77 recites wherein steps a)-c) result in higher levels of delivery of one or more molecules of the complex into the immune cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a).
Claim 78 recites wherein steps a)-c) result in a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a).
Claim 80 recites wherein steps a)-c) result in higher levels of delivery of one or more molecules of the complex into the immune cell as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a).
The claims denote that not all of the method step(s) of (a), (b), and (c) using the recited condition parameters recited at a high level of generality is/are able to achieve the functional property(ies) of:
result in higher levels of delivery of one or more molecules of the complex into the cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a).
Either the functional properties recited in the terminal ‘wherein’ clauses is/are inherent properties, that naturally flows(s) from, the positively recited method step parameters (a), (b), and (c), or it is not, and something of the method step(s) experimental parameter(s) and/or complexes themselves must change.
To the extent they are not an inherent property of (that naturally flows from) having performed the method steps (a), (b), and (c), then the instant claims are considered indefinite for failing to recite the structure/function nexus and/or method step(s)/function nexus in order to achieve the functional properties recited in the terminal ‘wherein steps a)-c) result in…’ clauses.
Claim 81 recites wherein the complex is delivered to less than 25% of the cells when the cell suspension is passed through the constriction in accordance with step a) and contacted in accordance with step b) except that one or more of the two or more molecules are not pre-formed in the complex.
Either this is an inherent property of (that naturally flows from) the method step parameters of Claim 80, or it is not, and something of the method step(s) experimental parameter(s) and/or complexes themselves must change.
The claim denotes that not all of the method step parameters of Claim 80 necessarily and predictably achieve the functional properties recited in Claim 81.
To the extent it is not an inherent property of (that naturally flows from) the product/method of the independent claim, then the instant claim is considered indefinite for failing to recite the structure/function nexus and/or method step(s)/function nexus in order to achieve the functional properties recited in Claim 81.
The ‘wherein’ clause limitations merely state a functional characteristic without providing any indication about how the functional characteristic(s) is/are provided. The functional characteristic(s) do/does not follow from (is/are not an inherent property(ies) of) the structures and/or method step(s) experimental parameter(s) recited in steps (a), (b), and (c), so the ordinary artisan would not know what one or more variables are to be modified to a method comprising steps (a), (b), and (c) so as to necessarily and sufficiently provide the functional characteristic(s) recited in the terminal ‘wherein’ clauses and/or Claim 81.
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The limitations “higher levels of delivery” and/or “higher number of viable cells” is/are a functional property that is/are dependent upon many different variable parameters, including, but not limited to:
the type of target cell, recited at a high level of generality, that is to be modified by the method [parameter 1];
the type of complex comprising at least one first molecule recited at a high level of generality that is to non-covalently bind to the at least one first polypeptide, recited at a high level of generality [parameter 2];
the binding affinity of the at least first molecule recited at a high level of generality that is able to bind non-covalently to the first polypeptide [parameter 3];
the viscosity of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device, ranging between 0.89cP and 2.0cP, as measured at about 20C [parameter 4];
the ionic strength of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 5];
the osmolarity of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 6];
the pH of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 7];
the inclusion of an enormously vast genus of structurally undisclosed cell solution and/or complex solution ingredients as the they pass through the microfluidic device [parameter 8];
the inclusion of a vast genus of detergents, and their corresponding working concentrations, in the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 9];
the shear force of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 10]; and
the microfluidic pressure (psi) value of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 11].
Parameter 1
The target cell is recited at a high level of generality, and essentially encompasses all forms of life extant on the planet.
The specification discloses the cell may be prokaryotic, bacterial, archeal, eukaryotic, fungal, algal, plant, or animal [0014].
BBC News (bbc.com/news/science-environment-14616161; August 23, 2011) is considered relevant prior art for having taught that there is an estimated 8.7 million different species on the planet, comprising about 7.77 million animal species, about 610,000 fungal species, about 300,000 plant species, and about 40,000 protozoan species.
The claims are also broad for encompassing about 0.8 to 1.6 million species of prokaryotes (Louca et al, A census-based estimate of Earth’s bacterial and archaeal diversity, PLoS Biology 17(2): e3000106, 30 pages, doi.org/10.1371/journal.pbio.3000106, 2019).
Parameter 2
The complex comprises at least one polypeptide recited at a high level of generality non-covalently associated with at least one other molecule recited at a high level of generality.
The breadth of the claim encompasses an enormously vast genus of structurally distinct first and second molecules of the complex, including an enormously vast genus of structurally undisclosed polypeptides, an enormously vast genus of structurally undisclosed nucleic acids, an enormously vast genus of structurally undisclosed lipids, an enormously vast genus of structurally undisclosed carbohydrates, an enormously vast genus of structurally undisclosed small molecules, and an enormously vast genus of structurally undisclosed metal-containing compounds.
Parameter 3
The specification discloses the binding affinity may be about 1pM to about 1uM [0005].
Parameter 4
The independent claims recite the viscosity ranges between 0.89cP and 2.0cP, as measured at about 20C.
Parameter 5
The specification discloses the ionic strength may be between about 50mM to about 300mM [0008].
Parameter 6
The specification discloses the osmolarity may be between about 100 mOsm/L to about 500 mOsm/L [0009].
Parameter 7
The specification discloses the pH may be between about 5.5 to about 8.5 [0010].
Parameter 8
The specification discloses the inclusion of an enormously vast genus of structurally undisclosed cell culture mediums, buffers, salts, sugars, growth factors, animal derived products, bulking materials, detergents, surfactants, lubricants, vitamins, polypeptides, and/or an agent that impacts actin polymerization [0094].
Parameter 9
The specification discloses the inclusion of a vast genus of detergents [0058] present at a concentration of about 0.1% (w/v) to about 10% (w/v) [0006].
Parameter 10
The specification discloses the shear force may be about 1kPa to about 100kPa [0011].
Parameter 11
Examples 1-5 disclose the microfluidic pressures of 60 or 90psi.
Resina et al (Physico-Chemical Characteristics of Lipoplexes Influence Cell Uptake Mechanisms and Transfection Efficacy, PLoS ONE 4(6): e6058, 11 pages, June 2009; of record) is considered relevant prior art for having taught a method of transfecting complexes into a target mammalian host cell at temperatures of 4C and 37C (e.g. pg 3, col. 1, Methods). Resina et al taught that the uptake mechanism is thermos-dependent because endocytosis is an energy-dependent and temperature-dependent process, and thus does not take place at 4C (e.g pg 5, col. 1).
Rols et al (Temperature effects on electrotransfection of mammalian cells, Nucleic Acids Research 22(3): pg 540 only, 1994; of record) is considered relevant prior art for having taught a method of transfecting complexes into a target mammalian host cell at temperatures of 4C, 21C and 37C, whereby the viability of the mammalian cells at 4C is about 10% less than the viability at 21C (45% vs 55%), and about 30% less than the viability at 37C (e.g. Table 2, 45% vs 75%).
The claims fail to recite, and the specification fails to disclose, a first method of Claims 77-78 and 80 that does not result in higher levels of delivery of one or more molecules of the complex into the cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a), as opposed to a second method of Claims 77-78 and 80 that necessarily and predictably results in higher levels of delivery of one or more molecules of the complex into the cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a), for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first method of Claims 77-78 and 80 that does not result in higher levels of delivery of one or more molecules of the complex into the cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a), into a second method of Claims 77-78 and 80 that now necessarily and predictably results in higher levels of delivery of one or more molecules of the complex into the cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a), for example.
The claims fail to recite, and the specification fails to disclose, the structure/function nexus and/or method step/function nexus that does not yield the functional limitations of Claim 81, as opposed to the structure/function nexus and/or method step/function nexus that does yield the functional limitations of Claim 81.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first method of Claim 80 that does not result in the functional limitations of Claim 81, into a second method of Claim 80 that now necessarily and predictably results in the functional limitations of Claim 81, for example.
The recitation implies a genus of undisclosed reference structures and/or method step experimental parameters, including, but not limited to, parameters 1-11 above, from which “higher levels of delivery” and/or “higher number of viable cells” is achieved, let alone determined, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The instant claim as a whole does not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language of the independent claim.
Response to Arguments
Applicant argues that the newly presented Claims 77-78 and 80 render the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)). The claims suffer from indefiniteness because the method is recited at a high level of generality and the claim fails to recite what change(s) is/are to be made to the method, including, but not limited to, parameters 1-11 above, in order to achieve the recited functional results.
The claims fail to recite, and the specification fails to disclose, the structure/function nexus and/or method step/function nexus that does not yield the functional limitations of the Claims 77-78 and 80 terminal ‘wherein’ clauses and/or the functional limitations of Claim 81, as opposed to the structure/function nexus and/or method step/function nexus that does yield the functional limitations of the Claims 77-78 and 80 terminal ‘wherein’ clauses and/or the functional limitations of Claim 81.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first method of Claims 77-78 and 80 that does not result in the functional limitations of the Claims 77-78 and 80 terminal ‘wherein’ clauses and/or the functional limitations of Claim 81, into a second method of Claims 77-78 and 80 that now necessarily and predictably results in the functional limitations of the Claims 77-78 and 80 terminal ‘wherein’ clauses and/or the functional limitations of Claim 81.
When functional claim language is found indefinite, it typically lacks an adequate written description under §112(a), because an indefinite, unbounded functional limitation would cover a plurality of undisclosed structures and/or method steps of performing a function and indicate that the inventor has not provided sufficient disclosure to show possession of the invention. Thus, in most cases, a §112(b) rejection that is based on functional language having unclear (or no) claim boundaries should be accompanied by a rejection under §112(a) based on failure to provide a written description for the claim. See MPEP 2173.05(g).
8. Claim(s) 33, 36-37, 49, 65, 75-78, and 80-81 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.
Claims 77-78 and 80 recite a method for delivering a complex of two or more molecules into a cell, the method comprising the steps of:
a) forming a complex of two or more molecules,
wherein the two or more molecules of the complex are associated by a noncovalent interaction, and
wherein the complex comprises at least one polypeptide;
b) contacting a cell suspension comprising cells with the complex of two or more molecules at a temperature of about 20 °C; and
c) passing the cell suspension and the complex through a constriction at a temperature of about 20 °C,
wherein the cell suspension comprises a viscosity ranging between about 0.89 cP and about 2.0 cP as measured at about 20 °C,
wherein the constriction comprises a width in the smallest dimension of about 3 μm to about 8 μm.
Claim 77 recites wherein steps a)-c) result in higher levels of delivery of one or more molecules of the complex into the immune cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a).
Claim 78 recites wherein steps a)-c) result in a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a).
Claim 80 recites wherein steps a)-c) result in higher levels of delivery of one or more molecules of the complex into the immune cell as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a).
The claims denote that not all of the method step(s) of (a), (b), and (c) using the recited condition parameters recited at a high level of generality is/are able to achieve the functional property(ies) of:
result in higher levels of delivery of one or more molecules of the complex into the cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a).
Either the functional properties recited in the terminal ‘wherein’ clauses is/are inherent properties, that naturally flows(s) from, the positively recited method step parameters (a), (b), and (c), or it is not, and something of the method step(s) experimental parameter(s) and/or complexes themselves must change.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The limitations “higher levels of delivery” and/or “higher number of viable cells” is/are a functional property that is/are dependent upon many different variable parameters, including, but not limited to:
the type of target cell, recited at a high level of generality, that is to be modified by the method [parameter 1];
the type of complex comprising at least one first molecule recited at a high level of generality that is to non-covalently bind to the at least one first polypeptide, recited at a high level of generality [parameter 2];
the binding affinity of the at least first molecule recited at a high level of generality that is able to bind non-covalently to the first polypeptide [parameter 3];
the viscosity of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device, ranging between 0.89cP and 2.0cP, as measured at about 20C [parameter 4];
the ionic strength of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 5];
the osmolarity of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 6];
the pH of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 7];
the inclusion of an enormously vast genus of structurally undisclosed cell solution and/or complex solution ingredients as the they pass through the microfluidic device [parameter 8];
the inclusion of a vast genus of detergents, and their corresponding working concentrations, in the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 9];
the shear force of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 10]; and
the microfluidic pressure (psi) value of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 11].
Parameter 1
The target cell is recited at a high level of generality, and essentially encompasses all forms of life extant on the planet.
The specification discloses the cell may be prokaryotic, bacterial, archeal, eukaryotic, fungal, algal, plant, or animal [0014].
BBC News (bbc.com/news/science-environment-14616161; August 23, 2011) is considered relevant prior art for having taught that there is an estimated 8.7 million different species on the planet, comprising about 7.77 million animal species, about 610,000 fungal species, about 300,000 plant species, and about 40,000 protozoan species.
The claims are also broad for encompassing about 0.8 to 1.6 million species of prokaryotes (Louca et al, A census-based estimate of Earth’s bacterial and archaeal diversity, PLoS Biology 17(2): e3000106, 30 pages, doi.org/10.1371/journal.pbio.3000106, 2019).
Working Example 2 is directed to human T cells (e.g. [0206], “T cells suspensions are passed through… microfluidic chips”).
Working Example 3 is directed to human embryonic kidney (HEK) cells.
Working Example 4 is directed to human cancer/tumor (HeLa) cells.
Working Example 5 is directed to mouse T cells.
The specification fails to demonstrate the method performing as claimed on target bacterial, protozoan, archeal, fungal, algal, or plant cells.
At best, the specification supports mammalian cells.
Parameter 2
The claims are broad for encompassing an enormously vast genus of molecular complexes comprising at least one first molecule recited at a high level of generality non-covalently associated with at least one first polypeptide recited at a high level of generality.
The breadth of the claim encompasses an enormously vast genus of structurally distinct first and second molecules of the complex, including an enormously vast genus of structurally undisclosed polypeptides, an enormously vast genus of structurally undisclosed nucleic acids, an enormously vast genus of structurally undisclosed lipids, an enormously vast genus of structurally undisclosed carbohydrates, an enormously vast genus of structurally undisclosed small molecules, and an enormously vast genus of structurally undisclosed metal-containing compounds.
The breadth of the claimed polypeptide present in the complex of two or more molecules comprising at least one polypeptide that are to be complexed non-covalently with an infinite genus of structurally undisclosed nucleic acids, other polypeptides, other peptides, lipids, carbohydrates, small molecules, and/or metal-containing compounds (e.g. [0069]) [parameter 1] is an enormously vast genus, whereby the specification discloses the protein or polypeptide is “not limited to a minimum length” and may comprise one or more amino acid substitutions, insertions, and/or deletions [0050].
Tiessen et al (Mathematical modeling and comparison of protein size distribution in different plant, animal, fungal and microbial species reveals a negative correlation between protein size and protein number, thus providing insight into the evolution of proteomes, BMC Research Notes 5: e85, 23 pages, www.biomedcentral.com/1756-0500/5/85; available online 2012; of record) is considered relevant prior art for having taught that the average eukaryotic protein is about 472 amino acids in length (Abstract).
20^472 is an infinite genus of structurally undisclosed polypeptides that are to be complexed non-covalently with an infinite genus of structurally undisclosed nucleic acids, other polypeptides, other peptides, lipids, carbohydrates, small molecules, and/or metal-containing compounds (e.g. [0069]).
(www.calculator.net/exponent-calculator.html; last visited June 9, 2025; of record)
Parameter 3
The claims are broad for encompassing an enormously vast genus of binding affinities between the [parameter 1] at least one first molecule recited at a high level of generality non-covalently associated with at least one first polypeptide recited at a high level of generality.
The specification discloses the binding affinity may be about 1pM to about 1uM [0005].
Independent claims fail to recite the nexus of the binding affinity(ies) between the at least first molecule recited at a high level of generality [parameter 1] and the at least first polypeptide recited at a high level of generality [parameter 1].
Parameter 4
The independent claims recite the viscosity ranges between 0.89cP and 2.0cP, as measured at about 20C.
Tirtaatmadja et al (Rheology of dextran solutions, J. Non-Newtonian Fluid Mech. 97: 295–301, 2001; of record) is considered relevant prior art for having taught that measuring intrinsic viscosity varies amongst different researchers, as it is dependent the temperature and nature of the solvent (syn. “buffer or culture medium”), as well as the molecular weight of the dextran and degree of branching (e.g. pg 296, para 1).
The working examples (Examples 2-4) disclose co-delivering the complexes in a medium comprising OptiMEM (e.g. [0206]).
The specification fails to disclose the viscosity (cP) value of OptiMEM, let alone when measured at about 20C, e.g. 15C, 18C, 20C, 22C, or 25C.
The working example (Example 5) disclose co-delivering the complexes in a medium comprising RPMI (e.g. [0218]).
The specification fails to disclose the viscosity (cP) value of RPMI, let alone when measured at about 20C, e.g. 15C, 18C, 20C, 22C, or 25C.
Applicant fails to clarify the record on the cP values of OptiMEM and/or RPMI, let alone when measured at about 20C.
Poon (Measuring the density and viscosity of culture media for optimized computational fluid dynamics analysis of in vitro devices, bioRxiv doi.org/10.1101/2020.08.25.266221, 15 pages, available online August 25, 2020; of record) is considered relevant art for having taught that the viscosity of culture media is expected to be denser and more viscous than water because the higher solute content comprising sugars, inorganic salts, and serum proteins (e.g. pg 2). The presence of additional metabolites, growth factors, and proteins will naturally increase viscosity.
Poon taught culture medium viscosity values for DMEM and RPMI-1640 culture mediums, at 0%, 5%, 10%, and 20% serum, measured at a temperature of 37C, to range from 0.73 to 1.09 mPa.s (e.g. Table 2), which is an estimated equivalence of 0.73cP to 1.09cP (1cP = 1mPa.s). Even water, at 37C has a viscosity of 0.66 mPa.s (syn. 0.66cP).
(www.unitconverters.net/viscosity-dynamic/centipoise-to-pascal-second.htm; last visited June 10, 2025; of record).
Independent claims are vastly broader in scope than OptiMEM and/or RPMI in the solution composition formularies, and their corresponding viscosity (cP) values, comprising the molecular complex and target cells as they pass through the microfluidic device.
The claims fail to recite, and the specification fails to disclose, a first solution comprising one or more of parameters 4, 5, 6, 7, and/or 8 having a viscosity of 0.89cP when measured at about 20C, e.g. 15C, 18C, 20C, 22C, or 25C, as opposed to a second solution comprising one or more of parameters 4, 5, 6, 7, and/or 8 that has a viscosity of 0.95, 1.0, 1.15, 1.3, 1.5, 1.65, 1.85, and/or 2.0cP when measured at about 20C, e.g. 15C, 18C, 20C, 22C, or 25C, for example.
The claims fail to recite, and the specification fails to disclose, a first cell culture medium comprising one or more of parameters 4, 5, 6, 7, and/or 8 having a viscosity of 0.89cP when measured at about 20C, e.g. 15C, 18C, 20C, 22C, or 25C, as opposed to a second cell culture medium comprising one or more of parameters 4, 5, 6, 7, and/or 8 that has a viscosity of 0.95, 1.0, 1.15, 1.3, 1.5, 1.65, 1.85, and/or 2.0cP when measured at about 20C, e.g. 15C, 18C, 20C, 22C, or 25C, for example.
Parameter 5
The claims are broad for encompassing an enormously vast genus of ionic strengths of the molecular complex solution and/or the cellular solution, including the solution comprising both the molecular complex and the cells as they pass through the microfluidic device.
The specification discloses the ionic strength may be between about 50mM to about 300mM [0008].
The art recognizes that ionic strengths have a significant impact on the ability of molecules to form non-covalent interactions with each other.
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Independent claims fail to recite the ionic strength of the [parameter 1] complex solution, whereby those of ordinary skill in the art would immediately recognize that ionic strength has a significant impact on the [parameter 2] binding affinities for the ability of the genus of at least first molecules recited at a high level of generality [parameter 1] to non-covalently bind the genus of the first polypeptides recited at a high level of generality [parameter 1], thereby forming a complex in the, at least, claimed step (a) “forming a complex”.
Parameter 6
The claims are broad for encompassing an enormously vast genus of osmolarity values of the molecular complex solution and/or the cellular solution, including the solution comprising both the molecular complex and the cells as they pass through the microfluidic device.
The specification discloses the osmolarity may be between about 100 mOsm/L to about 500 mOsm/L [0009].
Independent claims fail to recite the osmolarity value of the complex solution and the target cells as they pass through the microfluidic device in method step (c).
Parameter 7
The claims are broad for encompassing an enormously vast genus of pH values of the molecular complex solution and/or the cellular solution, including the solution comprising both the molecular complex and the cells as they pass through the microfluidic device.
The specification discloses the pH may be between about 5.5 to about 8.5 [0010].
The art recognizes that pH has a significant impact on the ability of molecules to form non-covalent interactions with each other.
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Independent claims fail to recite the pH value of the [parameter 1] complex solution, whereby those of ordinary skill in the art would immediately recognize that pH has a significant impact on the [parameter 2] binding affinities for the ability of the genus of at least first molecules recited at a high level of generality [parameter 1] to non-covalently bind the genus of the first polypeptides recited at a high level of generality [parameter 1], thereby forming a complex in the, at least, claimed step (a) “forming a complex”.
Independent claims fail to recite the pH value of the complex solution and the target cells as they pass through the microfluidic device in method step (c).
Parameter 8
The claims are broad for encompassing an enormously vast genus of additional ingredients of the molecular complex solution and/or the cellular solution, including the solution comprising both the molecular complex and the cells as they pass through the microfluidic device.
The specification discloses such solutions may comprise an enormously vast genus of structurally undisclosed cell culture mediums, buffers, salts, sugars, growth factors, animal derived products, bulking materials, detergents, surfactants, lubricants, vitamins, polypeptides, and/or an agent that impacts actin polymerization [0094].
As discussed above, these additional ingredients change the ionic strength, viscosity, and/or pH of the solutions, and thus alter the stability of the molecular complex, the amount of molecular complex introduced into the target cell, and/or the viability of the target cell.
Independent claims fail to recite the formulary composition of the solution comprising the molecular complex and the target cells as they pass through the microfluidic device in method step (c).
Parameter 9
The claims are broad for encompassing an enormously vast genus of detergents present in the molecular complex solution and/or the cellular solution, including the solution comprising both the molecular complex and the cells as they pass through the microfluidic device.
The specification discloses inclusion of a vast genus of detergents [0058] present at a concentration of about 0.1% (w/v) to about 10% (w/v) [0006].
The art recognizes that detergents, and their working concentrations, have a significant impact on the ability of molecules to form non-covalent interactions with each other, as well as cell viability.
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Independent claims fail to recite the pH of the [parameter 1] complex solution, whereby those of ordinary skill in the art would immediately recognize that pH has a significant impact on the [parameter 2] binding affinities for the ability of the genus of at least first molecules recited at a high level of generality [parameter 1] to non-covalently bind the genus of the first polypeptides recited at a high level of generality [parameter 1], thereby forming a complex in the, at least, claimed step (a) “forming a complex”.
Independent claims fail to recite the detergent formulary of the solution comprising the molecular complex and the target cells as they pass through the microfluidic device in method step (c).
Parameter 10
The claims are broad for encompassing an enormously vast genus of shear forces as the solution comprising both the molecular complex and the cells are passed through the microfluidic device.
The specification discloses the shear force may be about 1kPa to about 100kPa [0011].
The art recognizes that shear forces can negative the formation and/or stability of non-covalent interactions and/or cell viability.
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Independent claims fail to recite the shear force of the [parameter 1] complex solution and the target cells as they pass through the microfluidic device in method step (c).
Parameter 11
The claims are broad for encompassing an enormously vast genus of microfluidic pressures as the solution comprising both the molecular complex and the cells are passed through the microfluidic device.
Examples 1-5 disclose the microfluidic pressures of 60 or 90psi.
The art recognizes that microfluidic pressures, like shear forces, can negative cell viability.
Independent claims fail to recite the microfluidic pressure (psi) of the [parameter 1] complex solution and the target cells as they pass through the microfluidic device in method step (c).
The ‘wherein’ clause limitations merely state a functional characteristic without providing any indication about how the functional characteristic(s) is/are provided. The functional characteristic(s) do/does not follow from (is/are not an inherent property(ies) of) the structures and/or method step(s) experimental parameter(s) recited in steps (a), (b), and (c), so the ordinary artisan would not know what one or more variables are to be modified to a method comprising steps (a), (b), and (c) so as to necessarily and sufficiently provide the functional characteristic(s) recited in the terminal ‘wherein’ clauses and/or Claim 81.
The claim denotes that not all of the methods performing the positively recited step (c) parameters of passing a cell suspension through a constriction width of about 3um to about 8um at a temperature of about 20C in a solution viscosity ranging between about 0.89cP and about 2.0cP is/are able to achieve the functional property(ies) of “result in higher levels of delivery of one or more molecules of the complex into the [immune] cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a)”.
The claims fail to recite, and the specification fails to disclose, a first method of Claims 77-78 and 80 that does not result in higher levels of delivery of one or more molecules of the complex into the cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a), as opposed to a second method of Claims 77-78 and 80 that necessarily and predictably results in higher levels of delivery of one or more molecules of the complex into the cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a), for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first method of Claims 77-78 and 80 that does not result in higher levels of delivery of one or more molecules of the complex into the cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a), into a second method of Claims 77-78 and 80 that now necessarily and predictably results in higher levels of delivery of one or more molecules of the complex into the cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a), for example.
The claims fail to recite, and the specification fails to disclose, the structure/function nexus and/or method step/function nexus that does not yield the functional limitations of Claim 81, as opposed to the structure/function nexus and/or method step/function nexus that does yield the functional limitations of Claim 81.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first method of Claim 80 that does not result in the functional limitations of Claim 81, into a second method of Claim 80 that now necessarily and predictably results in the functional limitations of Claim 81, for example.
Sharei et al (WO 13/059343; of record in parent application 16/068,631) is considered relevant prior art for having disclosed a method and a system for delivering a complex of two or more molecules into a cell, the method comprising the step of passing a cell suspension through a constriction,
wherein said constriction deforms the cell, thereby causing a perturbation of the cell such that the complex of molecules enters the cell, and
wherein said cell suspension is contacted with the complex of molecules (Abstract: Figure 1b).
Sharei et al disclosed wherein the complex of molecules comprises one or more polypeptides (pg 8, line 6, “proteins”), e.g. a complex of two or more molecules may comprise, e.g. fluorescein covalently conjugated BSA (pg 46, lines 24-28).
Sharei et al disclosed a working example using DNA-wrapped carbon nanotubes (pg 50, lines 24-25), whereby those of ordinary skill in the art previously recognized that the DNA encapsulates the carbon nanotubes non-covalently. Thus, Applicant himself had previously successfully demonstrated the use of the instantly claimed microfluidic platform to introduce macromolecular complexes comprising at least two, structurally distinct molecules non-covalently complexed with each other into the target host cells.
While Sharei et al disclosed that the method may be used to deliver known amounts of DNA sequences together with known amounts of enzymes (syn. polypeptides) that enhance DNA recombination (pg 8, lines 25-26), known amounts of RNA silencing molecules with known amounts of Dicer (syn. polypeptide) molecules (pg 9, lines 2-4), co-delivery of two molecules (dextran and apolipoprotein (syn. polypeptide)) able to enter the same host cell per the method (pg 46, lines 15-19; Example 2), and delivery of four transcription factors (syn. first, second, third, fourth polypeptides) in to the same host cell (pg 51, lines 23-24; pg 64, lines 29-30), Sharei et al do not disclose ipsis verbis that the at least first polypeptide in each working example is/are complexed with the other molecule(s), let alone complexed by non-covalent bonds.
While Sharei et al disclosed the method may be used to introduce individual molecules or complexed molecules into the target cells, Sharei et al is silent as to what modifications to the method comprising the step of passing a cell suspension through a constriction are required in order to achieve the instantly recited functional property of “…increased compared to a corresponding method…”.
Rols et al (Temperature effects on electrotransfection of mammalian cells, Nucleic Acids Research 22(3): pg 540 only, 1994; of record) is considered relevant prior art for having taught a method of transfecting complexes into a target mammalian host cell at temperatures of 4C, 21C and 37C, whereby the viability of the mammalian cells at 4C is about 10% less than the viability at 21C (45% vs 55%), and about 30% less than the viability at 37C (e.g. Table 2, 45% vs 75%).
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial solution recited at a high level of generality comprising cells recited at a high level of generality are to be contacted with a solution recited at a high level of generality comprising a non-covalent complex of a first protein recited at a high level of generality and a first molecule recited at a high level of generality, whereby the solution comprising the cells and non-covalent complex are placed in a microfluidic device and passed through a constriction width of about 3um to about 8um at a temperature of about 20C in a solution viscosity ranging between about 0.89cP and about 2.0cP, does not tell you anything at all about the nexus of the structural and/or method step parameters encompassed by the claims, including, but not limited to:
the enormously vast genus of essentially all cell types extant on the planet, including, but not limited to, prokaryotic, bacterial, archeal, eukaryotic, fungal, algal, plant, animal, or mammalian host cell [parameter 1];
the type of complex comprising the at least one first molecule recited at a high level of generality and the at least one first polypeptide recited at a high level of generality [parameter 2];
the binding affinity of the at least first molecule recited at a high level of generality that is able to bind non-covalently to the first polypeptide [parameter 3];
the viscosity of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device, ranging between 0.89cP and 2.0cP, as measured at about 20C [parameter 4];
the ionic strength of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 5];
the osmolarity of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 6];
the pH of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 7];
the inclusion of an enormously vast genus of structurally undisclosed cell solution and/or complex solution ingredients as the they pass through the microfluidic device [parameter 8];
the inclusion of a vast genus of detergents, and their corresponding working concentrations, in the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 9];
the shear force of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 10]; and
the microfluidic pressure (psi) value of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 11],
so as to necessarily and predictably achieve the functional property(ies) of “result in higher levels of delivery of one or more molecules of the complex into the [immune] cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a)”.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim an entire universe of structurally undisclosed buffer and culture medium formularies described only using functional language “a viscosity ranging between about 0.89cP and 2.0cP, as measured at about 20C”.
The record reflects that Applicant seeks to claim an entire universe of structurally undisclosed and unrecited method step experimental condition parameters in which the cells of essentially all extant species on the planet and complex are to be passed through the microfluidic device, described only using functional language “result in higher levels of delivery of one or more molecules of the complex into the [immune] cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a)”.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
While the working example discloses that the complexing conditions, including complex concentration, solution osmolarity, salt concentration, temperature, pH, serum and surfactant content, and viscosity are optimized [0206], the specification fails to disclose what these optimized parameter values are.
At best, the specification supports mammalian host cells, such as cancer/tumor cells, endodermal cells such as kidney cells, and immune cells such as T cells.
The instant specification fails to make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which they fail to disclose.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language of the independent claim.
Response to Arguments
Applicant argues that the independent claims reciting steps (a)-(c) describe the viability and/or delivery nexus.
Applicant’s argument(s) has been fully considered, but is not persuasive.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
In the instant case, knowing that the initial solution recited at a high level of generality comprising cells recited at a high level of generality are to be contacted with a solution recited at a high level of generality comprising a non-covalent complex of a first protein recited at a high level of generality and a first molecule recited at a high level of generality, whereby the solution comprising the cells and non-covalent complex are placed in a microfluidic device and passed through a constriction width of about 3um to about 8um at a temperature of about 20C in a solution viscosity ranging between about 0.89cP and about 2.0cP, does not tell you anything at all about the nexus of the structural and/or method step parameters encompassed by the claims, including, but not limited to:
the type of prokaryotic, bacterial, archeal, eukaryotic, fungal, algal, plant, animal, or mammalian host cell [parameter 1];
the type of complex comprising the at least one first molecule recited at a high level of generality and the at least one first polypeptide recited at a high level of generality [parameter 2];
the binding affinity of the at least first molecule recited at a high level of generality that is able to bind non-covalently to the first polypeptide [parameter 3];
the viscosity of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device, ranging between 0.89cP and 2.0cP, as measured at about 20C [parameter 4];
the ionic strength of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 5];
the osmolarity of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 6];
the pH of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 7];
the inclusion of an enormously vast genus of structurally undisclosed cell solution and/or complex solution ingredients as the they pass through the microfluidic device [parameter 8];
the inclusion of a vast genus of detergents, and their corresponding working concentrations, in the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 9];
the shear force of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 10]; and
the microfluidic pressure (psi) value of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 11],
so as to necessarily and predictably achieve the functional property(ies) of “result in higher levels of delivery of one or more molecules of the complex into the [immune] cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a)”.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim an entire universe of structurally undisclosed buffer and culture medium formularies described only using functional language “a viscosity ranging between about 0.89cP and 2.0cP, as measured at about 20C”.
The record reflects that Applicant seeks to claim an entire universe of structurally undisclosed and unrecited method step experimental condition parameters in which the cells of essentially all extant species on the planet and complex are to be passed through the microfluidic device, described only using functional language “result in higher levels of delivery of one or more molecules of the complex into the [immune] cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a)”.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
While the working example discloses that the complexing conditions, including complex concentration, solution osmolarity, salt concentration, temperature, pH, serum and surfactant content, and viscosity are optimized [0206], the specification fails to disclose what these optimized parameter values are.
At best, the specification supports the modification of mammalian host cells, such as cancer/tumor cells, endodermal cells such as kidney cells, and immune cells such as T cells.
Examples 1-2 fail to disclose a higher viability as compared to when one or more of the two or more molecules are not pre-formed in the complex of step (a).
Examples 1-2 fail to disclose a higher level of delivery as compared to when one or more of the two or more molecules are not pre-formed in the complex of step (a).
Example 3 discloses a higher level of delivery an antibody when complexed with a Cas9/gRNA ribonucleoprotein, as compared to when the antibody is not complexed to the Cas9/gRNA ribonucleoprotein, as the antibody/Cas9/gRNA “complex is larger than the antibody alone”.
Example 3 fails to disclose a higher viability as compared to when one or more of the two or more molecules are not pre-formed in the complex of step (a).
Example 4 discloses a similar delivery of streptavidin, either alone or when complexed with biotin (e.g. [0213], “It was observed that streptavidin delivery in the streptavidin alone….and 1:1 streptavidin-biotin complex condition… was similar”).
Example 4 fails to disclose a higher viability as compared to when one or more of the two or more molecules are not pre-formed in the complex of step (a).
While Example 5 discloses delivery of the SLP/SMA complex is higher when the cells are passed through the constriction width of 3um, as compared to no constriction (e.g. [0218], “without constriction”; [0219], “constriction-mediated delivery”), Example 5 fails to disclose a higher level of delivery of the SLP/SMA complex, after having performed steps (a)-(c), as compared to when one or more of the two or more molecules are not pre-formed in the complex of step (a), e.g. SLP alone or SMA alone.
While Example 5 discloses that mere incubation of T cells with SLP alone leads to high cellular toxicity (e.g. [0220]) and that without constriction, the viability of T cells at higher SLP concentrations was significantly decreased, Example 5 fails to disclose a higher viability of cells after having performed steps (a)-(c), as compared to when one or more of the two or more molecules are not pre-formed in the complex of step (a), e.g. SLP alone or SMA alone.
The cell viability appears to be a result-effective variable dependent upon the structural and functional nature of the first molecule and/or second molecule of the non-covalent complex and/or the type of target host cell that responds to said first molecule and/or second molecule of the non-covalent complex.
Instant claims recite the first molecule and/or second molecule of the non-covalent complex at a high level of generality, and thus the claims are not commensurate in scope to asserted secondary considerations disclosed by Example 5.
Instant claims recite the target cell at a high level of generality, and thus the claims are not commensurate in scope to asserted secondary considerations disclosed by Example 5.
The instant specification fails to make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which they fail to disclose.
Applicant argues that the specification discloses sufficient written description of the experimental parameters.
Applicant’s argument(s) has been fully considered, but is not persuasive. The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
9. Claims 33, 36-37, 49, 65, 75-78, and 80-81 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
The Examiner incorporates herein the above Priority discussion.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial solution recited at a high level of generality comprising cells recited at a high level of generality are to be contacted with a solution recited at a high level of generality comprising a non-covalent complex of a first protein recited at a high level of generality and a first molecule recited at a high level of generality, whereby the solution comprising the cells and non-covalent complex are placed in a microfluidic device and passed through a constriction width of about 3um to about 8um at a temperature of about 20C in a solution viscosity ranging between about 0.89cP and about 2.0cP, does not tell you anything at all about the nexus of the structural and/or method step parameters encompassed by the claims, including, but not limited to:
the type of prokaryotic, bacterial, archeal, eukaryotic, fungal, algal, plant, animal, or mammalian host cell [parameter 1];
the type of complex comprising the at least one first molecule recited at a high level of generality and the at least one first polypeptide recited at a high level of generality [parameter 2];
the binding affinity of the at least first molecule recited at a high level of generality that is able to bind non-covalently to the first polypeptide [parameter 3];
the viscosity of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device, ranging between 0.89cP and 2.0cP, as measured at about 20C [parameter 4];
the ionic strength of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 5];
the osmolarity of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 6];
the pH of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 7];
the inclusion of an enormously vast genus of structurally undisclosed cell solution and/or complex solution ingredients as the they pass through the microfluidic device [parameter 8];
the inclusion of a vast genus of detergents, and their corresponding working concentrations, in the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 9];
the shear force of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 10]; and
the microfluidic pressure (psi) value of the solution comprising the cells and the complex of two or molecules as they pass through the microfluidic device [parameter 11],
so as to necessarily and predictably achieve the functional property(ies) of “result in higher levels of delivery of one or more molecules of the complex into the [immune] cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a)”.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim an entire universe of structurally undisclosed buffer and culture medium formularies described only using functional language “a viscosity ranging between about 0.89cP and 2.0cP, as measured at about 20C”.
The record reflects that Applicant seeks to claim an entire universe of structurally undisclosed and unrecited method step experimental condition parameters in which the cells of essentially all extant species on the planet and complex are to be passed through the microfluidic device, described only using functional language “result in higher levels of delivery of one or more molecules of the complex into the [immune] cell and/or a higher number of viable cells as compared to when one or more of the two or more molecules are not pre-formed in the complex in step a)”.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
While the working example discloses that the complexing conditions, including complex concentration, solution osmolarity, salt concentration, temperature, pH, serum and surfactant content, and viscosity are optimized [0206], the specification fails to disclose what these optimized parameter values are.
At best, the specification supports mammalian host cells, such as cancer/tumor cells, endodermal cells such as kidney cells, and immune cells such as T cells.
The instant specification fails to make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which they fail to disclose.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language of the independent claim.
Response to Arguments
Applicant argues secondary consideration of having introduced into pluripotent stem cells a complex of an anti-Cas antibody non-covalently associated with a Cas9/sgRNA ribonucleoprotein complex in a solution having a viscosity ranging from 1-1.8 cP, and passing the cells/antibody-RNP complex through a constriction of about 6um, or having introduced into T cells a complex of an anti-Cas antibody non-covalently associated with a Cas9/sgRNA ribonucleoprotein complex in a solution having a viscosity ranging from 1-1.8 cP, and passing the cells/antibody-RNP complex through a constriction of about 4um (Remarks Made in Amendment, pg 15).
Applicant’s argument(s) has been fully considered, but is not persuasive.
Applicant’s asserted secondary considerations, which fail to disclose:
i) the physiological saline solution formulary and temperature(s) during the (b) contacting step;
ii) the temperature(s) (a) passing the cell suspension through a constriction; and
iii) whether the contacting step is performed before, during, or after the step (a) passing the cell suspension through a constriction.
Applicant’s secondary considerations fail to disclose the method step/functional property nexus of (c)(i) and/or (c)(ii).
Instant claims are far broader in scope than Applicant’s asserted secondary considerations, e.g. the type of complex of the two or more molecules.
At best, Examples 1-5 disclose contacting the cells with the complex prior to passing the cells through the constriction. Instant Claim 1 is far broader in scope than Examples 3-5.
Conclusion
10. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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