Abel, Robert et al.

Patent Trials and Appeals Board

Aug 9, 2019

14138186 - (D) (P.T.A.B. Aug. 9, 2019)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
14/138,186 12/23/2013 Robert Abel 17367-0025001 7318
26161 7590 08/09/2019
FISH & RICHARDSON P.C. (BO)
P.O. BOX 1022
MINNEAPOLIS, MN 55440-1022
EXAMINER
NEGIN, RUSSELL SCOTT
ART UNIT PAPER NUMBER
1631
NOTIFICATION DATE DELIVERY MODE
08/09/2019 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
PATDOCTC@fr.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte ROBERT ABEL and LINGLE WANG
__________

Appeal 2018-001665
Application 14/138,1861
Technology Center 1600
__________

Before FRANCISCO C. PRATS, JOHN G. NEW, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

TOWNSEND, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
computer-implemented method for computing a relative binding affinity
between a protein and a ligand, which have been rejected as directed to
patent ineligible subject matter. Oral argument was held on July 26, 2019.
We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
“Free energy is a fundamental molecular property that plays an
essential role in characterizing chemical and biological systems.” (Spec. 1.)

1 The Appellant is the Applicant, Schrödinger, Inc., which identifies itself as
the real party in interest(Appeal Br. 1.)
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“Computer modeling and simulations are often used in free energy studies.”
(Id.) “[T]he free energy difference between two well-delineated
thermodynamic states, or relative free energy, are often used as a study
system to provide insight to particular systems, such as a relative binding
affinity of a ligand predicated on the measured affinity of a different but
similar ligand (e.g., a congeneric ligand).” (Id.) The calculations in these
simulations, regardless of the mathematical model employed, consider the
energy differences that result from changes (“transformations”) that take
place in a molecule from an initial state to the end state of the molecule,
such as conformational change, topological change and/or replacement of
atoms. (Id.) Appellant’s invention is a computer-implemented method for
computing free energy differences between a reference state and a target
state. (Id. at 3.)
Claims 1 and 6–30 are on appeal. Claim 1 is representative and reads
as follows:
1. A computer-implemented method for computing a
relative binding affinity between a protein and a ligand based
on a free energy difference between a reference state and a
target state, wherein the reference state and target state each
correspond to a respective arrangement of the protein and
ligand that include a common set of atoms PAB, and wherein the
reference state further includes a set of atoms PA, the target
state further includes a set of atoms PB, the set PA being present
only in the reference state and not in the target state, and the set
PB being present only in the target state and not the reference
state, where there exist at least two atoms Aa and Ab, Aa and Ab
being either: (1) not valence-bonded to each other in the
reference state and valence-bonded in the target state, or (2)
valence-bonded to each other in reference state and not valence-
bonded to each other in the target state, the method comprising:
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(a) providing a topology, including the bonded
connections between the atoms and the relative spatial
arrangements of the atoms, for all the atoms in PA, PB, and PAB;
(b) determining one or more intermediate system states
along a transformation path between the reference state and the
target state, the transformation path defined by a coupling
parameter λ, that modulates the energies arising from inter-
atom interactions for each system state, the coupling parameter
λ including a plurality of components each having a value
belonging to [0,1] and modulating a different type of interaction
energy;
(c) performing, using at least one computer processor,
molecular simulations to obtain ensembles of micro-states for
the reference state, the target state, and the intermediate states,
wherein performing molecular simulations for each of the
system states includes calculating a bonded stretch interaction
energy between the atoms Aa and Ab, the bonded stretch
interaction energy being defined by a soft bond potential,
wherein the soft bond potential is a function of a bonded
stretch component, λsbs, of the coupling parameter λ, and does
not include any singular regions for all values of λsbs within
[0,1] and for all values of the distance r between Aa and Ab, the
soft bond potential further satisfies the following conditions:
when λsbs is within (0,1), the soft bond potential is flat when the
distance between Aa and Ab approaches infinity; when Aa and
Ab are not valence bonded in either the reference state or the
target state, the soft bond potential is flat and zero for all
distances between Aa and Ab; and when Aa and Ab are valence
bonded in either the target state or the reference state, the soft
bond potential reverts to a harmonic potential; and
wherein the soft bond potential is a function of (r – r0)2,
where r0 is the equilibrium distance between Aa and Ab, and is
expressed by:
Usbs (r,λsbs)= ½kf(λsbs)(r-r0)2 1/1+g(λsbs)α(k, λsbs)(r-r0)2
where k is a constant, and the functions f, g and α are each
continuous functions and satisfy the following conditions:
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f(λsbs = 0) = 0,
f(λsbs = 1) = 1,
g(λsbs = 0) = 1,
g(λsbs = 1) = 0,
α(k, λsbs <1) > 0;
(d) calculating, using at least one computer processor, the
free energy difference between the reference state and the target
state, by way of an analysis of the ensembles of micro-states
obtained at the target state, the reference state, and the
intermediate states; and
(e) determining a relative binding affinity for the protein
and ligand based on the calculated free energy difference.
(Appeal Br. 13–15.)

The following ground of rejection by the Examiner is before us on
review:
Claims 1 and 6–30 under 35 U.S.C. § 101 as being directed to non-
statutory subject matter.
DISCUSSION
Background
In arriving at the conclusion that the claimed invention is directed to
non-statutory subject matter, the Examiner finds that the claimed process
involves “mathematical manipulations and equations to calculate specific
soft bond potentials.” (Final Action 3.) The Examiner contends that the
claimed invention also recites the following judicial exceptions “providing a
topology of the spatial arrangement of atoms,” “determining intermediate
system states along a transformation path using a coupling parameter,” and
“calculating bond stretch energies between atoms.” (Ans. 2.) The Examiner
determines that “[t]he additional element(s) or combination of elements in
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the claim(s) other than the abstract idea . . . amount(s) to no more than:
implementing the algorithm on a computer.” (Final Action at 3–4; Ans. 3.)
The Examiner explains that “[v]iewed as a whole, these additional claim
element(s) do not provide meaningful limitation(s) to transform the abstract
idea into a patent eligible application of” it. (Final Action 4; Ans. 3.)
Appellant does not dispute the Examiner’s determination that the
claimed invention involves mathematical calculations. (Reply Br. 2.)
Appellant notes that “the equations characterize the atomic arrangements in
a new and non-obvious manner” that “facilitate[s] determining a relative
binding affinity for different arrangement of atoms in the protein and
ligand.” (Id.) According to Appellant, “the application of the soft bond
potential in the calculation . . . allows the molecule to hop back and forth
between the alternative scaffolds at intermediate lambda.” (Id. at 4.) That is
“the soft bond potential was specifically formulated by the inventors to
facilitate the stable calculation of the very molecular transformations that
involve ring openings or closings.” (Id.)
Thus, Appellant argue that the claimed invention entails “an
unconventional technological solution to a technical problem” and thus
“constitute[s] ‘something more’ than an abstract idea.” (Appeal Br. 7.) In
particular, explains Appellant, the invention
use[s] a computer to perform molecular simulations that
involve[] calculating a bonded stretch interaction energy
between atoms that are valence bonded in only one of a target
or reference state and calculating free energy differences
between these states, which allow a relative binding affinity for
the protein and ligand to be determined.
(Appeal Br. 8.) Appellant explains that determining the relative binding
affinity in this way “may be used for computational drug design and
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discovery” (id. at 11), and “makes the process of identifying more promising
new compounds in the modifications of known active compounds more
efficient, and makes it possible to screen a large number of candidate
modifications to identify promising candidates that previously had to be
synthesized and characterized” (id. at 8).

Analysis
35 U.S.C. § 101 defines patent eligible subject matter. The Supreme
Court has carved out exceptions to what would otherwise appear to be
within the literal scope of § 101. Alice Corp. Pty. Ltd. v. CLS Bank Int’l,
573 U.S. 208, 216 (2014). One of these exceptions are claims “directed to”
an abstract idea. Id. at 217. This appeal involves the abstract idea exception
to patent eligibility under section 101.
The Supreme Court has established a two-step framework for
“distinguishing patents that claim laws of nature, natural phenomena, and
abstract ideas from those that claim patent-eligible applications of those
concepts.” Id. “First, we determine whether the claims at issue are directed
to” a patent-ineligible concept. Id. If so, “we consider the elements of each
claim both individually and ‘as an ordered combination’ to determine
whether the additional elements ‘transform the nature of the claim’ into a
patent-eligible application.” Id. (quoting Mayo Collaborative Servs. v.
Prometheus Labs., Inc., 566 U.S. 66, 78–79 (2012)).
The United States Patent and Trademark Office (PTO) issued the
2019 Revised Patent Subject Matter Eligibility Guidance (“Guidance”),
indicating how the PTO would analyze patent eligibility under the Supreme
Court’s two-step framework. 84 Fed. Reg. 50-57 (January 7, 2019).
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Applying the Guidance, we agree with the Examiner that the pending claims
are directed to patent ineligible subject matter.
STEP 2A, Prong One:
Under the Guidance, in determining what concept a claim is “directed
to” in step one of the Supreme Court’s two-step framework, we first look to
whether the claim recites any judicial exceptions, such as a mathematical
concept (including mathematical relationships, mathematical formulas or
equations, mathematical calculations). Guidance at 52, 54 (Step 2A, Prong
One).
Appellant does not dispute that the claims involve mathematical
equations in the calculation of free energy differences between reference
state and target state that are used to determine a relative binding affinity for
the protein and ligand. (See, e.g., Appeal Br. 5–6, 8; Reply Br. 2.)
We note that such mathematical equations are employed in step (c)’s
performing molecular simulations to obtain ensembles of micro-states for
the reference state, the target state, and the intermediate states. This step
involves “calculating a bonded stretch interaction energy,” which energy is
“defined by a soft bond potential,” which potential is defined by a particular
equation. Step (d) also involves mathematical calculations, though the
specific equations used are not recited. The calculations are made to
determine the free energy difference between the reference state and the
target state, by way of an analysis of the ensembles of micro-states. The
Specification enumerates several methods that may be used in free energy
calculation by analyzing ensembles. (See, e.g., Spec. 32–33 (explaining that
the calculation of free energy by way of analysis of the ensembles can be
“performed, for example, by way of Bannet Acceptance Ratio (BAR) . . .
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Zwanzig averaging . . . Alternatively, . . . the derivative of the energy with
respect of the coupling vector λ”).) Appellant’s dependent claims recite the
use of such methods. (See, e.g., claims 21 and 22.)
We conclude that step (e) also involves mathematical calculations. In
particular, this step requires the determination of the relative binding affinity
based on the calculated free energy. Appellant’s Specification does not
explain how one determines the relative binding affinity from the calculation
of the free energies. However the preamble of claim 1 states that the method
“compute[s] a relative binding affinity between a protein and a ligand based
on a free energy difference between a reference state and a target state.”
Thus, we find that step (e) involves mathematical calculations.
STEP 2A, Prong Two:
Having made the determination that claim 1 recites mathematical
calculations, under the Guidance, we next examine whether there are
additional elements beyond the calculations that integrate those judicial
exceptions into a practical application. Under the Guidance, this is referred
to as the “Prong Two” inquiry under “Step 2A.” Guidance at 54–55. That
is, under the Prong Two analysis we look to whether the claim as a whole
“appl[ies], rel[ies] on, or use[s] the judicial exception in a manner that
imposes a meaningful limit on the judicial exception.” Id.
The additional steps of claim 1 that are not the mathematical concepts
are the pre-solution data gathering steps (a) and (b). These data collection
steps do not amount to significantly more than the abstract idea because they
are insignificant pre-solution activities. See Mayo, 566 U.S. at 79 (quoting
Parker v. Flook, 437 U.S. 584, 590 (1978)) (“Purely ‘conventional or
obvious’ ‘[pre]-solution activity’ is normally not sufficient to transform an
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unpatentable law of nature into a patent-eligible application of such a law”);
see also Guidance, 55, n.31. Indeed, determining values for variables used
in mathematical formulae does not save a claim from abstraction. In re
Richman, 563 F.2d 1026, 1030 (1977) (“[N]otwithstanding that the
antecedent steps are novel and unobvious, they merely determine values for
the variables used in the mathematical formulae used in making the
calculations. [They] do not suffice to render the claimed methods,
considered as a whole, statutory subject matter.”) (cited with approval in
Flook, 437 U.S. at 595).
We find that the focus of the claim is on the judicially excepted
subject matter — the mathematical calculations which allow one to compute
relative binding affinity for the protein and ligand based on the calculated
free energy difference by analysis of the ensemble of micro-states along a
transformation path. Indeed, Appellant explains that the claimed invention
improves “the computational efficiency and convergence of the free energy
calculations” between a reference state and a target state of protein and
ligand interaction. (Appeal Br. 6.) As inventor Dr. Abel states, the
improvement derives from the soft bond potential equation recited in the
claim compared with “prior art bond potential[] [calculations].” (Abel
Declaration dated January 22, 2016, ¶¶ 7, 12 (“Abel First Dec.”); Abel
Second Declaration dated August 8, 2016 ¶ 9 (“Abel Second Dec.”).)
Indeed, Dr. Abel states that “the claimed algorithm” is the “improved
technique for determining free energy differences between two states.”
(Abel First Dec. ¶ 7; see also Abel Second Dec. ¶ 9 (“Use of the ‘soft bond
potential’ as claimed in calculations . . . allow[s] chemists to
computationally score changes to the ring size of a core of a molecule and
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score the introduction of new rings in to the core of a molecule” enabling
“chemists to pursue scaffold-hopping modifications with greater confidence
the resulting molecules will be potent, speeding up and lowering the cost of
drug discovery projects.”).)
In this respect, this case is like Flook. In Flook, the “only difference
between the conventional methods of changing alarm limits and that
described in respondent’s application rest[ed] in the second step–the
mathematical algorithm or formula.” 437 U.S. at 585–86. The Supreme
Court found that the claimed subject matter “simply provides a new and
presumably better method for calculating alarm limit values” and, thus, was
not directed to patent eligible subject matter. Id. at 595 (explaining “‘if a
claim is directed essentially to a method of calculating, using a mathematical
formula, even if the solution is for a specific purpose, the claimed method is
nonstatutory.”’). The Supreme Court found that the use of this method to
adjust an alarm limit did not render the method patent eligible. Id.
Here, as in Flook, the claimed method is directed essentially to a “new
and presumably better” algorithm, and the only difference between the
claimed method and conventional methods lies in the algorithms used.
(Accord Spec. at 19 (“the soft bond potential removes the singularity and
numerical instability problems associated with the traditional methods . . .
Using the soft bond potential described herein, the free energy difference
between the reference system state and the target system state involving
breaking and form valance bond can be accurately and reliabl[y]
calculated.”).) As in Flook, the judicially excepted subject matter generates
information (the free energy differences, in Flook, an alarm value). In
Flook, the information generated was used to “adjust” an alarm value. Here,
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the information generated is not even used to adjust anything, but simply to
assess a state of being, i.e., the binding affinity between protein and ligand.
In that assessment, just as in the case of Flook’s adjustment of the alarm
limit, the use of the information generated by the excepted subject matter
does not integrate the judicially excepted subject matter into a practical
application. Compare Ex Parte Roelle, 2017-011336, 2019 WL 2385915,
*5–*7 (PTAB May 30, 2019) (reversing a § 101 rejection for a claim
reciting a method for preparing a photopolymer formulation where a series
of mathematical calculations are used to select an appropriate compound for
use as a plasticizer in preparing that photopolymer formulation, because the
“claim . . . as a whole transforms a set of individual compounds––a matrix
polymer, a writing monomer, a photoinitiator, and a plasticizer—into a
photopolymer composition”)
Appellant asserts that claim 1 entails an “unconventional
technological solution to a technical problem” (Appeal Br. 7) because the
claim uses mathematical calculations that are novel (Appeal Br. 8) in
determining relative binding affinity. That is not the kind of “technological”
improvement that suffices for patent eligibility. See Amdocs Ltd. v. Openet
Telecom, Inc., 841 F.3d 1288, 1300, 1302 (Fed. Cir. 2016) (the claim
“entail[ed] an unconventional technological solution (enhancing data in a
distributed fashion) to a technological problem (massive record flows [that]
previously required massive databases)” that “improve[d] the performance
of the system itself.”) The novelty of the mathematical calculation is not
sufficient to establish a practical application. See SAP Am., Inc. v. Investpic,
LLC, 898 F.3d 1161, 1163 (Fed. Cir. 2018) (finding that an invention that is
nothing more than “a series of mathematical calculations based on selected
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information and the presentation of the results of those calculations” is
patent-ineligible). Flook, 437 U.S. at 591–95 (1978) (“[R]espondent’s claim
is, in effect, comparable to a claim that the formula 2πr can be usefully
applied in determining the circumference of a wheel. As the Court of
Customs and Patent Appeals has explained, ‘if a claim is directed essentially
to a method of calculating, using a mathematical formula, even if the
solution is for a specific purpose, the claimed method is nonstatutory.’ In re
Richman, 563 F.2d 1026, 1030 (1977).”)
Here, claim 1 does not rely on the judicial exception in such a way to
impose a meaningful limitation thereon. Rather it limits the use of the
judicial exception to a particular environment. “Flook stands for the
proposition that the prohibition against patenting abstract ideas cannot be
circumvented by attempting to limit the use of [the idea] to a particular
technological environment.” Alice, 573 U.S. at 222–23 (quoting Bilski v.
Kappos, 561 U.S. 593, 610–611 (2010) (internal quotation marks omitted).
Appellant’s reliance on the decision in Amdocs (Israel) Ltd. v. Openet
Telecom, Inc., 841 F.3d 1288 (Fed. Cir. 2016)(App. Br. 7–8) is unavailing.
There, the court held that a claim directed to using accounting information
with which a network accounting record is correlated to enhance the record
was held eligible because the claim involved an unconventional
technological solution (enhancing data in a distributed fashion) to a
technological problem (massive record flows which previously required
massive databases). Although the court recognized that this solution used
generic components, the recited enhancing function necessarily required
these generic components to operate in an unconventional manner to achieve
an improvement in computer functionality. Id. at 1300–01. Notably, the
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recited enhancement in Amdocs depended on not only the network’s
distributed architecture, but also on the network devices and “gatherers”
working together in a distributed environment. Id. at 1301.2
Likewise, Appellant’s reliance on Diamond v. Diehr, 450 U.S. 175
(1981) (Appeal Br. 10) is not persuasive. The Court in Diehr found that a
claim employing a mathematical formula in a manufacturing process was
patent eligible, because it “applie[d] that formula in a structure or process
which, when considered as a whole, [was] performing a function which the
patent laws were designed to protect (e.g., transforming or reducing an
article to a different state or thing).” Diehr, 450 U.S. at 192; see Thales
Visionix Inc. v. United States, 850 F.3d 1343, 1348 (Fed. Cir. 2017) (“In
terms of the modem day Alice test, the Diehr claims were directed to an
improvement in the rubber curing process, not a mathematical formula.”).

2 Appellant also refers us to Appeal No. 2015-006279, a non-precedential
decision determining that claims to a method for identifying potential
modifications to peptides associated with a precursor peptide were not
directed to patent ineligible subject matter. We note that we are not bound
by non-precedential Board opinions made in a different proceeding on a
different patent. The claims of the patent in the referred to Board opinion
are not the same as presented here. Moreover, in that Appeal, the Board
noted that the claimed invention was tied to a structure, and were not
persuaded that the claim limitations considered as an ordered combination,
“recite[d] an invention that is merely the routine or conventional use of
technology previously known to skilled persons.” 2016 WL 6903672 *2.
Here, Appellant’s claim merely uses a general purpose computer as a tool to
perform an abstract idea, which is not indicative that the abstract idea has
been integrated into a practical application. See, e.g., Guidance at 55; Alice,
573 U.S. at 223–24 (quoting Mayo, 566 U.S. at 77) (“[W]holly generic
computer implementation is not generally the sort of ‘additional featur[e]’
that provides any ‘practical assurance that the process is more than a drafting
effort designed to monopolize the [abstract idea] itself.’”).
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Unlike the industrial process for the molding of rubber products claimed in
Diehr, claim 1 is merely a computational method for determining relative
binding affinity between a protein and a ligand based on a free energy
difference between a reference state and a target state. While Appellant
contends that determination “may be used for computational drug design and
discovery” (Appeal Br. 11), claim 1 does not recite any practical application
of the mathematical determination.
Appellant’s reliance on Thales Visionix Inc. v. United States, 850 F.3d
1343 (2017) (Appeal Br. 11; Reply Br. 2) is likewise unavailing. In Thales,
the court held eligible claims reciting determining an orientation of an object
relative to a moving reference frame based on signals from two inertial
sensors mounted respectively on the object and on the moving reference
frame. Id. at 1345–49. In reaching its eligibility conclusion, the court noted
that the claimed invention used inertial sensors in an unconventional manner
to reduce errors in measuring a moving object’s relative position and
orientation on a moving reference frame. Id. at 1348–49.
STEP 2B
Step 2B requires that we look to whether the claim “adds a specific
limitation beyond the judicial exception that [is] not ‘well-understood,
routine, conventional’ in the field.” (see MPEP § 2106.05(d)). We do not
doubt Appellant’s contention that the claimed mathematical process
employed to determine relative binding affinity between a protein and a
ligand “which the Examiner concedes is ‘free of the prior art’” (Appeal Br.
9) is unconventional. However, that unconventionality is part of the judicial
exception itself. Appellant makes no argument that there is anything about
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the claimed method other than the mathematical calculations that is
unconventional.
Appellant’s argument that “claim 1 does not preempt every method of
all ways of calculating relative binding affinities” (Appeal Br. 9) is also
unavailing. Preemption concerns are fully addressed and made moot where
a patent’s claims are deemed to disclose patent-ineligible subject matter
under the two-part framework described in Mayo and Alice. Ariosa
Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1379 (Fed. Cir. 2015)
(“While preemption may signal patent ineligible subject matter, the absence
of complete preemption does not demonstrate patent eligibility.”).
In light of the foregoing, we conclude that the claim 1 is directed to no
more than judicial exceptions to Section 101 and do not recite the
“significantly more” requisite to transform the nature of the claim into a
patent-eligible application, as required by Mayo. We consequently affirm
the Examiner’s rejection upon this ground.
Claims 6–30 have not been argued separately and therefore fall with
claim 1. 37 C.F.R. § 41.37(c)(1)(iv).

SUMMARY
We affirm the rejection of claims 1 and 6–30 under 35 U.S.C. § 101
as being directed to non-statutory subject matter.
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TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED